Publications by authors named "Susan A Allen"

31 Publications

Elevated levels of inflammatory plasma biomarkers are associated with risk of HIV infection.

Retrovirology 2021 03 17;18(1). Epub 2021 Mar 17.

Emory Vaccine Center at Yerkes National Primate Research Center, Atlanta, GA, USA.

Background: To determine if individuals, from HIV-1 serodiscordant couple cohorts from Rwanda and Zambia, who become HIV-positive have a distinct inflammatory biomarker profile compared to individuals who remain HIV-negative, we compared levels of biomarkers in plasma of HIV-negative individuals who either seroconverted (pre-infection) and became HIV-positive or remained HIV-negative (uninfected).

Results: We observed that individuals in the combined cohort, as well as those in the individual country cohorts, who later became HIV-1 infected had significantly higher baseline levels of multiple inflammatory cytokines/chemokines compared to individuals who remained HIV-negative. Genital inflammation/ulceration or schistosome infections were not associated with this elevated profile. Defined levels of ITAC and IL-7 were significant predictors of later HIV acquisition in ROC predictive analyses, whereas the classical Th1 and Th2 inflammatory cytokines such as IL-12 and interferon-γ or IL-4, IL-5 and Il-13 were not.

Conclusions: Overall, the data show a significant association between increased plasma biomarkers linked to inflammation and immune activation and HIV acquisition and suggests that pre-existing conditions that increase systemic biomarkers represent a factor for increased risk of HIV infection.
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http://dx.doi.org/10.1186/s12977-021-00552-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968240PMC
March 2021

HIV-1 variants are archived throughout infection and persist in the reservoir.

PLoS Pathog 2020 06 3;16(6):e1008378. Epub 2020 Jun 3.

Emory Vaccine Center, Emory University, Atlanta, Georgia, United States of America.

The HIV-1 reservoir consists of latently infected cells that persist despite antiretroviral therapy (ART). Elucidating the proviral genetic composition of the reservoir, particularly in the context of pre-therapy viral diversity, is therefore important to understanding reservoir formation and the persistence of latently infected cells. Here we investigate reservoir proviral variants from 13 Zambian acutely-infected individuals with additional pre-therapy sampling for a unique comparison to the ART-naïve quasispecies. We identified complete transmitted/founder (TF) viruses from seroconversion plasma samples, and additionally amplified and sequenced HIV-1 from plasma obtained one year post-infection and just prior to ART initiation. While the majority of proviral variants in the reservoir were most closely related to viral variants from the latest pre-therapy time point, we also identified reservoir proviral variants dating to or near the time of infection, and to intermediate time points between infection and treatment initiation. Reservoir proviral variants differing by five or fewer nucleotide changes from the TF virus persisted during treatment in five individuals, including proviral variants that exactly matched the TF in two individuals, one of whom had remained ART-naïve for more than six years. Proviral variants during treatment were significantly less divergent from the TF virus than plasma variants present at the last ART-naïve time point. These findings indicate that reservoir proviral variants are archived throughout infection, recapitulating much of the viral diversity that arises throughout untreated HIV-1 infection, and strategies to target and reduce the reservoir must therefore permit for the clearance of proviruses encompassing this extensive diversity.
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http://dx.doi.org/10.1371/journal.ppat.1008378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295247PMC
June 2020

Protective HLA alleles are associated with reduced LPS levels in acute HIV infection with implications for immune activation and pathogenesis.

PLoS Pathog 2019 08 26;15(8):e1007981. Epub 2019 Aug 26.

Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.

Despite extensive research on the mechanisms of HLA-mediated immune control of HIV-1 pathogenesis, it is clear that much remains to be discovered, as exemplified by protective HLA alleles like HLA-B*81 which are associated with profound protection from CD4+ T cell decline without robust control of early plasma viremia. Here, we report on additional HLA class I (B*1401, B*57, B*5801, as well as B*81), and HLA class II (DQB1*02 and DRB1*15) alleles that display discordant virological and immunological phenotypes in a Zambian early infection cohort. HLA class I alleles of this nature were also associated with enhanced immune responses to conserved epitopes in Gag. Furthermore, these HLA class I alleles were associated with reduced levels of lipopolysaccharide (LPS) in the plasma during acute infection. Elevated LPS levels measured early in infection predicted accelerated CD4+ T cell decline, as well as immune activation and exhaustion. Taken together, these data suggest novel mechanisms for HLA-mediated immune control of HIV-1 pathogenesis that do not necessarily involve significant control of early viremia and point to microbial translocation as a direct driver of HIV-1 pathogenesis rather than simply a consequence.
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http://dx.doi.org/10.1371/journal.ppat.1007981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730937PMC
August 2019

HLA Class I Downregulation by HIV-1 Variants from Subtype C Transmission Pairs.

J Virol 2018 04 14;92(7). Epub 2018 Mar 14.

Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA

HIV-1 downregulates human leukocyte antigen A (HLA-A) and HLA-B from the surface of infected cells primarily to evade CD8 T cell recognition. HLA-C was thought to remain on the cell surface and bind inhibitory killer immunoglobulin-like receptors, preventing natural killer (NK) cell-mediated suppression. However, a recent study found HIV-1 primary viruses have the capacity to downregulate HLA-C. The goal of this study was to assess the heterogeneity of HLA-A, HLA-B, and HLA-C downregulation among full-length primary viruses from six chronically infected and six newly infected individuals from transmission pairs and to determine whether transmitted/founder variants exhibit common HLA class I downregulation characteristics. We measured HLA-A, HLA-B, HLA-C, and total HLA class I downregulation by flow cytometry of primary CD4 T cells infected with 40 infectious molecular clones. Primary viruses mediated a range of HLA class I downregulation capacities (1.3- to 6.1-fold) which could differ significantly between transmission pairs. Downregulation of HLA-C surface expression on infected cells correlated with susceptibility to NK cell suppression of virus release. Despite this, transmitted/founder variants did not share a downregulation signature and instead were more similar to the quasispecies of matched donor partners. These data indicate that a range of viral abilities to downregulate HLA-A, HLA-B, and HLA-C exist within and between individuals that can have functional consequences on immune recognition. Subtype C HIV-1 is the predominant subtype involved in heterosexual transmission in sub-Saharan Africa. Authentic subtype C viruses that contain natural sequence variations throughout the genome often are not used in experimental systems due to technical constraints and sample availability. In this study, authentic full-length subtype C viruses, including transmitted/founder viruses, were examined for the ability to disrupt surface expression of HLA class I molecules, which are central to both adaptive and innate immune responses to viral infections. We found that the HLA class I downregulation capacity of primary viruses varied, and HLA-C downregulation capacity impacted viral suppression by natural killer cells. Transmitted viruses were not distinct in the capacity for HLA class I downregulation or natural killer cell evasion. These results enrich our understanding of the phenotypic variation existing among natural HIV-1 viruses and how that might impact the ability of the immune system to recognize infected cells in acute and chronic infection.
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http://dx.doi.org/10.1128/JVI.01633-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972908PMC
April 2018

Transitioning couple's voluntary HIV counseling and testing (CVCT) from stand-alone weekend services into routine antenatal and VCT services in government clinics in Zambia's two largest cities.

PLoS One 2017 16;12(10):e0185142. Epub 2017 Oct 16.

Rwanda Zambia HIV Research Group, Department of Pathology & Laboratory Medicine, School of Medicine and Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, United States of America.

Introduction: Most HIV infections in Africa are acquired by married/cohabiting adults and WHO recommends couple's voluntary HIV counseling and testing (CVCT) for prevention. The handover from NGO-sponsored weekend CVCT to government-sponsored services in routine weekday antenatal care (ANC) and individual voluntary testing and counseling (VCT) services in Zambia's two largest cities from 2009-2015 is described.

Methods: Government clinic counselors were trained to provide CVCT, and along with community health workers they promoted CVCT services in their clinic and surrounding areas. When client volume exceeded the capacity of on-duty staff in ANC and VCT, non-governmental organization (NGO) subsidies were offered for overtime pay.

Results: Implementation of routine CVCT services varied greatly by clinic and city. The 12 highest volume clinics were examined further, while 13 clinics had CVCT numbers that were too low to warrant further investigation. In Lusaka, the proportion of pregnant women whose partners were tested rose from 2.6% in 2009 to a peak of 26.2% in 2012 and 24.8% in 2015. Corresponding reports in Ndola were 2.0% in 2009, 17.0% in 2012 and 14.5% in 2015. Obstacles to CVCT included: limited space and staffing, competing priorities, record keeping not adapted for couples, and few resources for promotion and increasing male involvement. Conflicting training models for 'partner testing' with men and women separately vs. CVCT with joint post-test counseling led to confusion in reporting to district health authorities.

Discussion: A focused and sustained effort will be required to reach a meaningful number of couples with CVCT to prevent heterosexual and perinatal HIV transmission. Establishing targets and timelines, funding for dedicated and appropriately trained staff, adoption of standardized data recording instruments with couple-level indicators, and expansion of community and clinic-based promotions using proven models are recommended.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0185142PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642897PMC
October 2017

HIV Incidence and Predictors of HIV Acquisition From an Outside Partner in Serodiscordant Couples in Lusaka, Zambia.

J Acquir Immune Defic Syndr 2017 10;76(2):123-131

*Rwanda Zambia HIV Research Group, Department of Pathology and Laboratory Medicine, School of Medicine, Rollins School of Public Health, Emory University, Atlanta, GA; †Department of Epidemiology, Fielding School of Public Health, UCLA, Los Angeles, CA; ‡Department of Epidemiology, Rollins School of Public Health, Laney Graduate School, Emory University, Atlanta, GA; §Department of Epidemiology, Ryals School of Public Health, University of Alabama at Birmingham, Birmingham, AL; ‖Department of Gynecology and Obstetrics, School of Medicine, University of Zambia, Lusaka, Zambia; and ¶Ministry of Community Development, Mother and Child Health, Lusaka, Zambia.

Objective: Evaluate the incidence and predictors of HIV acquisition from outside partners in serodiscordant couples.

Methods: Demographic, behavioral, and clinical exposures were measured quarterly in a cohort of serodiscordant cohabiting couples in Zambia from 1995 to 2012 (n = 3049). Genetic analysis classified incident infections as those acquired from the study partner (linked) or acquired from an outside partner (unlinked). Factors associated with time to unlinked HIV infection were evaluated using multivariable Cox proportional hazards regression stratified by sex.

Results: There were 100 unlinked infections in couples followed for a median of 806 days. Forty-five infections occurred in women [1.85/100 couple-years; 95% confidence interval (CI): 1.35 to 2.47]. Risk of female unlinked infection (vs. nonseroconverting females) was associated with reporting being drunk weekly/daily vs. moderate/nondrinkers at baseline [adjusted hazard ratio (aHR) = 5.44; 95% CI: 1.03 to 28.73], genital ulcers (aHR = 6.09; 95% CI: 2.72 to 13.64), or genital inflammation (aHR = 11.92; 95% CI: 5.60 to 25.37) during follow-up adjusting for age, years cohabiting, income, contraceptive use, previous pregnancies, history of sexually transmitted infections, and condomless sex with study partner. Fifty-five infections occurred in men (1.82/100 couple-years; 95% CI: 1.37 to 2.37). Risk of male unlinked infection was associated with genital inflammation (aHR = 8.52; 95% CI: 3.82 to 19.03) or genital ulceration (aHR = 2.31; 95% CI: 2.05 to 8.89), reporting ≥1 outside sexual partner (aHR = 3.86; 95% CI: 0.98 to 15.17) during follow-up, and reporting being drunk weekly/daily vs. moderate/nondrinkers at baseline (aHR = 3.84; 95% CI: 1.28 to 11.55), controlling for age, income, circumcision status, and history of sexually transmitted infection.

Conclusions: Predictors of unlinked infection in serodiscordant relationships were alcohol use, genital inflammation, and ulceration. Causes of genital inflammation and ulceration should be screened for and treated in HIV-negative individuals. Counseling on risk of alcohol use and sex with outside partners should be discussed with couples where 1 or both are HIV-negative, including in counseling on use of pre-exposure prophylaxis to prevent HIV acquisition in the HIV-negative partner (when feasible and affordable).
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http://dx.doi.org/10.1097/QAI.0000000000001494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5597474PMC
October 2017

Couples' voluntary HIV counseling and testing provider training evaluation, Zambia.

Health Promot Int 2018 Aug;33(4):580-588

Rwanda Zambia HIV Research Group, Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, Georgia, USA.

With the expansion of couples' voluntary HIV counseling and testing (CVCT) in urban Zambia, there is a growing need to evaluate CVCT provider trainings to ensure that couples are receiving quality counseling and care. We evaluated provider knowledge scores, pre- and post-training and predictors of pre- and post-training test scores. Providers operating in 67 government clinics in four Copperbelt Province cities were trained from 2008 to 2013 in three domains: counseling, rapid HIV laboratory testing and data management. Trainees received pre- and post-training tests on domain-specific topics. Pre- and post-training test scores were tabulated by provider demographics and training type, and paired t-tests evaluated differences in pre- and post-training test scores. Multivariable ANCOVA determined predictors of pre- and post-training test scores. We trained 1226 providers, and average test scores increased from 68.8% pre-training to 83.8% post-training (p < 0.001). Test scores increased significantly for every demographic group and training type (p < 0.001) with one exception-test scores did not significantly increase for those receiving counseling or data management training who had less than a high school education. In multivariable analysis, higher educational level and having a medical background were predictive of a higher pre-test score; higher pre-test scores and having a medical background were predictive of higher post-test scores. Pre- and post-test assessments are critical to ensure quality services, particularly as task-shifting from medical to lay staff becomes more common. Assessments showed that our CVCT trainings are successful at increasing knowledge, and that those with lower education may benefit from repeat trainings.
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http://dx.doi.org/10.1093/heapro/daw108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144772PMC
August 2018

Promotion of couples' voluntary HIV counseling and testing: a comparison of influence networks in Rwanda and Zambia.

BMC Public Health 2016 08 8;16:744. Epub 2016 Aug 8.

Rwanda Zambia HIV Research Group (RZHRG), Department of Pathology & Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA, USA.

Background: Many African adults do not know that partners in steady or cohabiting relationships can have different HIV test results. Despite WHO recommendations for couples' voluntary counseling and testing (CVCT), fewer than 10 % of couples have been jointly tested and counseled. We examine the roles and interactions of influential network leaders (INLs) and influential network agents (INAs) in promoting CVCT in Kigali, Rwanda and Lusaka, Zambia.

Methods: INLs were identified in the faith-based, non-governmental, private, and health sectors. Each INL recruited and mentored several INAs who promoted CVCT. INLs and INAs were interviewed about demographic characteristics, promotional efforts, and working relationships. We also surveyed CVCT clients about sources of CVCT information.

Results: In Zambia, 53 INAs and 31 INLs were surveyed. In Rwanda, 33 INAs and 27 INLs were surveyed. Most (75 %-90 %) INAs believed that INL support was necessary for their promotional work. Zambian INLs reported being more engaged with their INAs than Rwandan INLs, with 58 % of Zambian INLs reporting that they gave a lot of support to their INAs versus 39 % in Rwanda. INAs in both Rwanda and Zambia reported promoting CVCT via group forums (77 %-97 %) and speaking to a community leader about CVCT (79 %-88 %) in the past month. More Rwandan INAs and INLs reported previous joint or individual HIV testing compared with their Zambian counterparts, of which more than half had not been tested. In Zambia and Rwanda, 1271 and 3895 CVCT clients were surveyed, respectively. Hearing about CVCT from INAs during one-on-one promotions was the most frequent source of information reported by clients in Zambia (71 %). In contrast, Rwandan couples who tested were more likely to have heard about CVCT from a previously tested couple (59 %).

Conclusions: CVCT has long been endorsed for HIV prevention but few couples have been reached. Influential social networks can successfully promote evidence-based HIV prevention in Africa. Support from more senior INLs and group presentations leveraged INAs' one-on-one promotions. The INL/INA model was effective in promoting couples to seek joint HIV testing and counseling and may have broader application to other sub-Saharan African countries to sustainably increase CVCT uptake.
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http://dx.doi.org/10.1186/s12889-016-3424-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4977827PMC
August 2016

Heterosexual Transmission of Subtype C HIV-1 Selects Consensus-Like Variants without Increased Replicative Capacity or Interferon-α Resistance.

PLoS Pathog 2015 Sep 17;11(9):e1005154. Epub 2015 Sep 17.

Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.

Heterosexual transmission of HIV-1 is characterized by a genetic bottleneck that selects a single viral variant, the transmitted/founder (TF), during most transmission events. To assess viral characteristics influencing HIV-1 transmission, we sequenced 167 near full-length viral genomes and generated 40 infectious molecular clones (IMC) including TF variants and multiple non-transmitted (NT) HIV-1 subtype C variants from six linked heterosexual transmission pairs near the time of transmission. Consensus-like genomes sensitive to donor antibodies were selected for during transmission in these six transmission pairs. However, TF variants did not demonstrate increased viral fitness in terms of particle infectivity or viral replicative capacity in activated peripheral blood mononuclear cells (PBMC) and monocyte-derived dendritic cells (MDDC). In addition, resistance of the TF variant to the antiviral effects of interferon-α (IFN-α) was not significantly different from that of non-transmitted variants from the same transmission pair. Thus neither in vitro viral replicative capacity nor IFN-α resistance discriminated the transmission potential of viruses in the quasispecies of these chronically infected individuals. However, our findings support the hypothesis that within-host evolution of HIV-1 in response to adaptive immune responses reduces viral transmission potential.
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http://dx.doi.org/10.1371/journal.ppat.1005154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574710PMC
September 2015

Implementation of an electronic fingerprint-linked data collection system: a feasibility and acceptability study among Zambian female sex workers.

Global Health 2015 Jun 27;11:27. Epub 2015 Jun 27.

Rwanda Zambia HIV Research Group, Department of Pathology and Laboratory Medicine, School of Medicine and Hubert Department of Global Health, Rollins School of Public Health, Emory University, 1518 Clifton Road NE, CNR 4011, Atlanta, GA, 30322, USA.

Background: Patient identification within and between health services is an operational challenge in many resource-limited settings. When following HIV risk groups for service provision and in the context of vaccine trials, patient misidentification can harm patient care and bias trial outcomes. Electronic fingerprinting has been proposed to identify patients over time and link patient data between health services. The objective of this study was to determine 1) the feasibility of implementing an electronic-fingerprint linked data capture system in Zambia and 2) the acceptability of this system among a key HIV risk group: female sex workers (FSWs).

Methods: Working with Biometrac, a US-based company providing biometric-linked healthcare platforms, an electronic fingerprint-linked data capture system was developed for use by field recruiters among Zambian FSWs. We evaluated the technical feasibility of the system for use in the field in Zambia and conducted a pilot study to determine the acceptability of the system, as well as barriers to uptake, among FSWs.

Results: We found that implementation of an electronic fingerprint-linked patient tracking and data collection system was feasible in this relatively resource-limited setting (false fingerprint matching rate of 1/1000 and false rejection rate of <1/10,000) and was acceptable among FSWs in a clinic setting (2% refusals). However, our data indicate that less than half of FSWs are comfortable providing an electronic fingerprint when recruited while they are working. The most common reasons cited for not providing a fingerprint (lack of privacy/confidentiality issues while at work, typically at bars or lodges) could be addressed by recruiting women during less busy hours, in their own homes, in the presence of "Queen Mothers" (FSW organizers), or in the presence of a FSW that has already been fingerprinted.

Conclusions: Our findings have major implications for key population research and improved health services provision. However, more work needs to be done to increase the acceptability of the electronic fingerprint-linked data capture system during field recruitment. This study indicated several potential avenues that will be explored to increase acceptability.
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http://dx.doi.org/10.1186/s12992-015-0114-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489038PMC
June 2015

Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4+ T cells, and disease progression.

Proc Natl Acad Sci U S A 2015 Mar 17;112(12):E1480-9. Epub 2015 Feb 17.

Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322;

HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1-induced immunopathology and subsequent CD4(+) T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8(+) T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4(+) T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1-related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.
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http://dx.doi.org/10.1073/pnas.1421607112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4378387PMC
March 2015

Transmitted virus fitness and host T cell responses collectively define divergent infection outcomes in two HIV-1 recipients.

PLoS Pathog 2015 Jan 8;11(1):e1004565. Epub 2015 Jan 8.

Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America; Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.

Control of virus replication in HIV-1 infection is critical to delaying disease progression. While cellular immune responses are a key determinant of control, relatively little is known about the contribution of the infecting virus to this process. To gain insight into this interplay between virus and host in viral control, we conducted a detailed analysis of two heterosexual HIV-1 subtype A transmission pairs in which female recipients sharing three HLA class I alleles exhibited contrasting clinical outcomes: R880F controlled virus replication while R463F experienced high viral loads and rapid disease progression. Near full-length single genome amplification defined the infecting transmitted/founder (T/F) virus proteome and subsequent sequence evolution over the first year of infection for both acutely infected recipients. T/F virus replicative capacities were compared in vitro, while the development of the earliest cellular immune response was defined using autologous virus sequence-based peptides. The R880F T/F virus replicated significantly slower in vitro than that transmitted to R463F. While neutralizing antibody responses were similar in both subjects, during acute infection R880F mounted a broad T cell response, the most dominant components of which targeted epitopes from which escape was limited. In contrast, the primary HIV-specific T cell response in R463F was focused on just two epitopes, one of which rapidly escaped. This comprehensive study highlights both the importance of the contribution of the lower replication capacity of the transmitted/founder virus and an associated induction of a broad primary HIV-specific T cell response, which was not undermined by rapid epitope escape, to long-term viral control in HIV-1 infection. It underscores the importance of the earliest CD8 T cell response targeting regions of the virus proteome that cannot mutate without a high fitness cost, further emphasizing the need for vaccines that elicit a breadth of T cell responses to conserved viral epitopes.
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http://dx.doi.org/10.1371/journal.ppat.1004565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4287535PMC
January 2015

Low antibody-dependent cellular cytotoxicity responses in Zambians prior to HIV-1 intrasubtype C superinfection.

Virology 2014 Aug 5;462-463:295-8. Epub 2014 Jul 5.

Emory Vaccine Center at Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, GA 30329, USA; Department of Pathology and Laboratory Medicine, Emory University, 101, Woodruff Circle, Atlanta, GA 30322, USA. Electronic address:

We have previously shown that HIV-1 superinfected Zambian seroconverters mount low binding and neutralizing antibody responses to their primary HIV-1 infecting virus, which could increase susceptibility to re-infection. Here, we investigated if antibody-dependent cellular cytotoxicity (ADCC), a process by which virus-infected cells are killed, was also reduced. Superinfected individuals exhibited low ADCC activity compared to non-superinfected individuals, but similar levels of CMV-reactive binding antibodies, suggesting superinfected individuals are capable of generating and maintaining virus-specific antibodies.
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http://dx.doi.org/10.1016/j.virol.2014.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125417PMC
August 2014

Disease progression by infecting HIV-1 subtype in a seroconverter cohort in sub-Saharan Africa.

AIDS 2013 Nov;27(17):2775-86

aInternational AIDS Vaccine Initiative, New York, New York, USA bProject San Francisco, Kigali, Rwanda cMedical Research Council/Uganda Virus Research Unit, Research Unit on AIDS, Entebbe, Uganda dBiostatistics Consultant, Arlington, Virginia, USA eCentre for Geographic Medicine-Coast/Kenya Medical Research Institute, Kilifi, Kenya fUniversity of Oxford, Oxford, UK gZambia-Emory HIV Research Project, Lusaka, Zambia hKenya AIDS Vaccine Initiative, University of Nairobi, Nairobi, Kenya iAurum Institute, Rustenburg jDesmond Tutu HIV Centre, University of Cape Town, Cape Town, Republic of South Africa kEmory University, Atlanta, Georgia, USA lIAVI Human Immunology Laboratory, Imperial College, London, UK.

Objective: To describe immunologic, virologic, and clinical HIV disease progression by HIV-1 subtype among Africans with well documented estimated dates of HIV infection (EDIs).

Design: Prospective cohort.

Methods: Adults and youth with documented HIV-1 infection in the past 12 months were recruited from seroincidence cohorts in East and Southern Africa and followed at 3-6 month intervals. Blood for lymphocyte subset and viral load determination was collected at each visit. Pol was sequenced from the first positive specimen to ascertain subtype. Preantiretroviral therapy disease progression was measured by three time-to-event endpoints: CD4 cell count 350 cells/μl or less, viral load measurement at least 1 × 10 copies/ml, and clinical AIDS.

Results: From 2006 to 2011, 615 participants were enrolled at nine research centers in Kenya, Rwanda, South Africa, Uganda, and Zambia; 579 (94.1%) had viral subtyping completed. Predominant subtypes were C (256, 44.2%), A (209, 36.1%), and D (84, 14.5%). After adjustment for age, sex, and human leukocyte antigen alleles in Cox regression analyses, subtype C-infected participants progressed faster than subtype A to all three endpoints [CD4 hazard ratio 1.60, 95% (confidence interval) CI 1.16, 2.20; viral load hazard ratio 1.59, 95% CI 1.12, 2.25; and AIDS hazard ratio 1.60, 95% CI 1.11, 2.31). Subtype D-infected participants reached high viral load more rapidly (hazard ratio 1.61, 95% CI 1.01, 2.57) and progressed nearly twice as fast to AIDS compared to subtype A (hazard ratio 1.93, 95% CI 1.21, 3.09).

Conclusion: Subtype-specific differences in HIV disease progression suggest that the local subtype distribution be considered when planning HIV programs and designing and defining clinical endpoints for HIV prevention trials.
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http://dx.doi.org/10.1097/QAD.0000000000000012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3815107PMC
November 2013

Viral escape from neutralizing antibodies in early subtype A HIV-1 infection drives an increase in autologous neutralization breadth.

PLoS Pathog 2013 Feb 28;9(2):e1003173. Epub 2013 Feb 28.

Immunology and Molecular Pathogenesis Graduate Program, Emory University, Atlanta, Georgia, United States of America.

Antibodies that neutralize (nAbs) genetically diverse HIV-1 strains have been recovered from a subset of HIV-1 infected subjects during chronic infection. Exact mechanisms that expand the otherwise narrow neutralization capacity observed during early infection are, however, currently undefined. Here we characterized the earliest nAb responses in a subtype A HIV-1 infected Rwandan seroconverter who later developed moderate cross-clade nAb breadth, using (i) envelope (Env) glycoproteins from the transmitted/founder virus and twenty longitudinal nAb escape variants, (ii) longitudinal autologous plasma, and (iii) autologous monoclonal antibodies (mAbs). Initially, nAbs targeted a single region of gp120, which flanked the V3 domain and involved the alpha2 helix. A single amino acid change at one of three positions in this region conferred early escape. One immunoglobulin heavy chain and two light chains recovered from autologous B cells comprised two mAbs, 19.3H-L1 and 19.3H-L3, which neutralized the founder Env along with one or three of the early escape variants carrying these mutations, respectively. Neither mAb neutralized later nAb escape or heterologous Envs. Crystal structures of the antigen-binding fragments (Fabs) revealed flat epitope contact surfaces, where minimal light chain mutation in 19.3H-L3 allowed for additional antigenic interactions. Resistance to mAb neutralization arose in later Envs through alteration of two glycans spatially adjacent to the initial escape signatures. The cross-neutralizing nAbs that ultimately developed failed to target any of the defined V3-proximal changes generated during the first year of infection in this subject. Our data demonstrate that this subject's first recognized nAb epitope elicited strain-specific mAbs, which incrementally acquired autologous breadth, and directed later B cell responses to target distinct portions of Env. This immune re-focusing could have triggered the evolution of cross-clade antibodies and suggests that exposure to a specific sequence of immune escape variants might promote broad humoral responses during HIV-1 infection.
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http://dx.doi.org/10.1371/journal.ppat.1003173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585129PMC
February 2013

Role of transmitted Gag CTL polymorphisms in defining replicative capacity and early HIV-1 pathogenesis.

PLoS Pathog 2012 29;8(11):e1003041. Epub 2012 Nov 29.

Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, United States of America.

Initial studies of 88 transmission pairs in the Zambia Emory HIV Research Project cohort demonstrated that the number of transmitted HLA-B associated polymorphisms in Gag, but not Nef, was negatively correlated to set point viral load (VL) in the newly infected partners. These results suggested that accumulation of CTL escape mutations in Gag might attenuate viral replication and provide a clinical benefit during early stages of infection. Using a novel approach, we have cloned gag sequences isolated from the earliest seroconversion plasma sample from the acutely infected recipient of 149 epidemiologically linked Zambian transmission pairs into a primary isolate, subtype C proviral vector, MJ4. We determined the replicative capacity (RC) of these Gag-MJ4 chimeras by infecting the GXR25 cell line and quantifying virion production in supernatants via a radiolabeled reverse transcriptase assay. We observed a statistically significant positive correlation between RC conferred by the transmitted Gag sequence and set point VL in newly infected individuals (p = 0.02). Furthermore, the RC of Gag-MJ4 chimeras also correlated with the VL of chronically infected donors near the estimated date of infection (p = 0.01), demonstrating that virus replication contributes to VL in both acute and chronic infection. These studies also allowed for the elucidation of novel sites in Gag associated with changes in RC, where rare mutations had the greatest effect on fitness. Although we observed both advantageous and deleterious rare mutations, the latter could point to vulnerable targets in the HIV-1 genome. Importantly, RC correlated significantly (p = 0.029) with the rate of CD4+ T cell decline over the first 3 years of infection in a manner that is partially independent of VL, suggesting that the replication capacity of HIV-1 during the earliest stages of infection is a determinant of pathogenesis beyond what might be expected based on set point VL alone.
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http://dx.doi.org/10.1371/journal.ppat.1003041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510241PMC
April 2013

Fertility goal-based counseling increases contraceptive implant and IUD use in HIV-discordant couples in Rwanda and Zambia.

Contraception 2013 Jul 12;88(1):74-82. Epub 2012 Nov 12.

Rwanda Zambia HIV Research Group, Department of Pathology and Laboratory Medicine, School of Medicine, Emory University, Atlanta, GA 30322, USA.

Background: HIV-discordant heterosexual couples are faced with the dual challenge of preventing sexual HIV transmission and unplanned pregnancies with the attendant risk of perinatal HIV transmission. Our aim was to examine uptake of two long-acting reversible contraceptive (LARC) methods--intrauterine devices (IUD) and hormonal implants--among HIV-discordant couples in Rwanda and Zambia.

Study Design: Women were interviewed alone or with their partner during routine cohort study follow-up visits to ascertain fertility goals; those not pregnant, not infertile, not already using LARC, and wishing to limit or delay fertility for ≥3 years were counseled on LARC methods and offered an IUD or implant on-site.

Results: Among 409 fertile HIV-discordant Rwandan women interviewed (126 alone, 283 with partners), 365 (89%) were counseled about LARC methods, and 130 (36%) adopted a method (100 implant, 30 IUD). Of 787 fertile Zambian women interviewed (457 alone, 330 with partners), 528 (67%) received LARC counseling, of whom 177 (34%) adopted a method (139 implant, 38 IUD). In both countries, a woman's younger age was predictive of LARC uptake. LARC users reported fewer episodes of unprotected sex than couples using only condoms.

Conclusions: Integrated fertility goal-based family planning counseling and access to LARC methods with reinforcement of dual-method use prompted uptake of IUDs and implants and reduced unprotected sex among HIV-discordant couples in two African capital cities.
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http://dx.doi.org/10.1016/j.contraception.2012.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625675PMC
July 2013

HIV-1 subtype C superinfected individuals mount low autologous neutralizing antibody responses prior to intrasubtype superinfection.

Retrovirology 2012 Sep 20;9:76. Epub 2012 Sep 20.

Immunology and Molecular Pathogenesis Graduate Program, Emory University, Atlanta, GA, USA.

Background: The potential role of antibodies in protection against intra-subtype HIV-1 superinfection remains to be understood. We compared the early neutralizing antibody (NAb) responses in three individuals, who were superinfected within one year of primary infection, to ten matched non-superinfected controls from a Zambian cohort of subtype C transmission cases. Sequence analysis of single genome amplified full-length envs from a previous study showed limited diversification in the individuals who became superinfected with the same HIV-1 subtype within year one post-seroconversion. We hypothesized that this reflected a blunted NAb response, which may have made these individuals more susceptible to superinfection.

Results: Neutralization assays showed that autologous plasma NAb responses to the earliest, and in some cases transmitted/founder, virus were delayed and had low to undetectable titers in all three superinfected individuals prior to superinfection. In contrast, NAbs with a median IC50 titer of 1896 were detected as early as three months post-seroconversion in non-superinfected controls. Early plasma NAbs in all subjects showed limited but variable levels of heterologous neutralization breadth. Superinfected individuals also exhibited a trend toward lower levels of gp120- and V1V2-specific IgG binding antibodies but higher gp120-specific plasma IgA binding antibodies.

Conclusions: These data suggest that the lack of development of IgG antibodies, as reflected in autologous NAbs as well as gp120 and V1V2 binding antibodies to the primary infection virus, combined with potentially competing, non-protective IgA antibodies, may increase susceptibility to superinfection in the context of settings where a single HIV-1 subtype predominates.
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http://dx.doi.org/10.1186/1742-4690-9-76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477039PMC
September 2012

Timing and source of subtype-C HIV-1 superinfection in the newly infected partner of Zambian couples with disparate viruses.

Retrovirology 2012 Mar 20;9:22. Epub 2012 Mar 20.

Emory Vaccine Center at Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.

Background: HIV-1 superinfection occurs at varying frequencies in different at risk populations. Though seroincidence is decreased, in the negative partner of HIV-discordant couples after joint testing and counseling in the Zambia Emory HIV Research Project (ZEHRP) cohort, the annual infection rate remains relatively high at 7-8%. Based on sequencing within the gp41 region of each partner's virus, 24% of new infections between 2004 and 2008 were the result of transmission from a non-spousal partner. Since these seroconvertors and their spouses have disparate epidemiologically-unlinked viruses, there is a risk of superinfection within the marriage. We have, therefore, investigated the incidence and viral origin of superinfection in these couples.

Results: Superinfection was detected by heteroduplex mobility assay (HMA), degenerate base counting of the gp41 sequence, or by phylogenetic analysis of the longitudinal sequences. It was confirmed by full-length env single genome amplification and phylogenetic analysis. In 22 couples (44 individuals), followed for up to five years, three of the newly infected (initially HIV uninfected) partners became superinfected. In each case superinfection occurred during the first 12 months following initial infection of the negative partner, and in each case the superinfecting virus was derived from a non-spousal partner. In addition, one probable case of intra-couple HIV-1 superinfection was observed in a chronically infected partner at the time of his seroconverting spouse's initial viremia. Extensive recombination within the env gene was observed following superinfection.

Conclusions: In this subtype-C discordant couple cohort, superinfection, during the first year after HIV-1 infection of the previously negative partner, occurred at a rate similar to primary infection (13.6% [95% CI 5.2-34.8] vs 7.8% [7.1-8.6]). While limited intra-couple superinfection may in part reflect continued condom usage within couples, this and our lack of detecting newly superinfected individuals after one year of primary infection raise the possibility that immunological resistance to intra-subtype superinfection may develop over time in subtype C infected individuals.
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http://dx.doi.org/10.1186/1742-4690-9-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349552PMC
March 2012

Knowledge and perceptions of couples' voluntary counseling and testing in urban Rwanda and Zambia: a cross-sectional household survey.

PLoS One 2011 May 9;6(5):e19573. Epub 2011 May 9.

Project San Francisco, Rwanda Zambia HIV Research Group, Kigali, Rwanda.

Background: Most incident HIV infections in sub-Saharan Africa occur between cohabiting, discordant, heterosexual couples. Though couples' voluntary HIV counseling and testing (CVCT) is an effective, well-studied intervention in Africa, <1% of couples have been jointly tested.

Methods: We conducted cross-sectional household surveys in Kigali, Rwanda (n = 600) and Lusaka, Zambia (n = 603) to ascertain knowledge, perceptions, and barriers to use of CVCT.

Results: Compared to Lusaka, Kigali respondents were significantly more aware of HIV testing sites (79% vs. 56%); had greater knowledge of HIV serodiscordance between couples (83% vs. 43%); believed CVCT is good (96% vs. 72%); and were willing to test jointly (91% vs. 47%). Stigma, fear of partner reaction, and distance/cost/logistics were CVCT barriers.

Conclusions: Though most respondents had positive attitudes toward CVCT, the majority were unaware that serodiscordance between cohabiting couples is possible. Future messages should target gaps in knowledge about serodiscordance, provide logistical information about CVCT services, and aim to reduce stigma and fear.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0019573PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3090401PMC
May 2011

Lack of detectable HIV-1-specific CD8(+) T cell responses in Zambian HIV-1-exposed seronegative partners of HIV-1-positive individuals.

J Infect Dis 2011 Jan 9;203(2):258-62. Epub 2010 Dec 9.

Ragon Institute of MGH, MIT and Harvard, Charlestown, Massachusetts 02129-2000, USA.

Human immunodeficiency virus type 1 (HIV-1)-specific T cell responses were characterized in a blinded study involving infected individuals and their seronegative exposed uninfected (EU) partners from Lusaka, Zambia. HIV-1-specific T cell responses were detected ex vivo in all infected individuals and amplified, on average, 27-fold following in vitro expansion. In contrast, no HIV-1-specific T cell responses were detected in any of the EU partners ex vivo or following in vitro expansion. These data demonstrate that the detection of HIV-1-specific T cell immunity in EU individuals is not universal and that alternative mechanisms may account for protection in these individuals.
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http://dx.doi.org/10.1093/infdis/jiq028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071055PMC
January 2011

Couples' voluntary counselling and testing and nevirapine use in antenatal clinics in two African capitals: a prospective cohort study.

J Int AIDS Soc 2010 Mar 15;13:10. Epub 2010 Mar 15.

Emory University, Atlanta, Georgia, USA.

Background: With the accessibility of prevention of mother to child transmission (PMTCT) services in sub-Saharan Africa, more women are being tested for HIV in antenatal care settings. Involving partners in the counselling and testing process could help prevent horizontal and vertical transmission of HIV. This study was conducted to assess the feasibility of couples' voluntary counseling and testing (CVCT) in antenatal care and to measure compliance with PMTCT.

Methods: A prospective cohort study was conducted over eight months at two public antenatal clinics in Kigali, Rwanda, and Lusaka, Zambia. A convenience sample of 3625 pregnant women was enrolled. Of these, 1054 women were lost to follow up. The intervention consisted of same-day individual voluntary counselling and testing (VCT) and weekend CVCT; HIV-positive participants received nevirapine tablets. In Kigali, nevirapine syrup was provided in the labour and delivery ward; in Lusaka, nevirapine syrup was supplied in pre-measured single-dose syringes. The main outcome measures were nurse midwife-recorded deliveries and reported nevirapine use.

Results: In eight months, 1940 women enrolled in Kigali (984 VCT, 956 CVCT) and 1685 women enrolled in Lusaka (1022 VCT, 663 CVCT). HIV prevalence was 14% in Kigali, and 27% in Lusaka. Loss to follow up was more common in Kigali than Lusaka (33% vs. 24%, p = 0.000). In Lusaka, HIV-positive and HIV-negative women had significantly different loss-to-follow-up rates (30% vs. 22%, p = 0.002). CVCT was associated with reduced loss to follow up: in Kigali, 31% of couples versus 36% of women testing alone (p = 0.011); and in Lusaka, 22% of couples versus 25% of women testing alone (p = 0.137). Among HIV-positive women with follow up, CVCT had no impact on nevirapine use (86-89% in Kigali; 78-79% in Lusaka).

Conclusions: Weekend CVCT, though new, was feasible in both capital cities. The beneficial impact of CVCT on loss to follow up was significant, while nevirapine compliance was similar in women tested alone or with their partners. Pre-measured nevirapine syrup syringes provided flexibility to HIV-positive mothers in Lusaka, but may have contributed to study loss to follow up. These two prevention interventions remain a challenge, with CVCT still operating without supportive government policy in Zambia.
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http://dx.doi.org/10.1186/1758-2652-13-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2851580PMC
March 2010

Escape from autologous neutralizing antibodies in acute/early subtype C HIV-1 infection requires multiple pathways.

PLoS Pathog 2009 Sep 18;5(9):e1000594. Epub 2009 Sep 18.

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA, USA.

One aim for an HIV vaccine is to elicit neutralizing antibodies (Nab) that can limit replication of genetically diverse viruses and prevent establishment of a new infection. Thus, identifying the strengths and weaknesses of Nab during the early stages of natural infection could prove useful in achieving this goal. Here we demonstrate that viral escape readily occurred despite the development of high titer autologous Nab in two subjects with acute/early subtype C infection. To provide a detailed portrayal of the escape pathways, Nab resistant variants identified at multiple time points were used to create a series of envelope (Env) glycoprotein chimeras and mutants within the background of a corresponding newly transmitted Env. In one subject, Nab escape was driven predominantly by changes in the region of gp120 that extends from the beginning of the V3 domain to the end of the V5 domain (V3V5). However, Nab escape pathways in this subject oscillated and at times required cooperation between V1V2 and the gp41 ectodomain. In the second subject, escape was driven by changes in V1V2. This V1V2-dependent escape pathway was retained over time, and its utility was reflected in the virus's ability to escape from two distinct monoclonal antibodies (Mabs) derived from this same patient via introduction of a single potential N-linked glycosylation site in V2. Spatial representation of the sequence changes in gp120 suggested that selective pressure acted upon the same regions of Env in these two subjects, even though the Env domains that drove escape were different. Together the findings argue that a single mutational pathway is not sufficient to confer escape in early subtype C HIV-1 infection, and support a model in which multiple strategies, including potential glycan shifts, direct alteration of an epitope sequence, and cooperative Env domain conformational masking, are used to evade neutralization.
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http://dx.doi.org/10.1371/journal.ppat.1000594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2741593PMC
September 2009

Inflammatory genital infections mitigate a severe genetic bottleneck in heterosexual transmission of subtype A and C HIV-1.

PLoS Pathog 2009 Jan 23;5(1):e1000274. Epub 2009 Jan 23.

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, United States of America.

The HIV-1 epidemic in sub-Saharan Africa is driven largely by heterosexual transmission of non-subtype B viruses, of which subtypes C and A are predominant. Previous studies of subtype B and subtype C transmission pairs have suggested that a single variant from the chronically infected partner can establish infection in their newly infected partner. However, in subtype A infected individuals from a sex worker cohort and subtype B individuals from STD clinics, infection was frequently established by multiple variants. This study examined over 1750 single-genome amplified viral sequences derived from epidemiologically linked subtype C and subtype A transmission pairs very early after infection. In 90% (18/20) of the pairs, HIV-1 infection is initiated by a single viral variant that is derived from the quasispecies of the transmitting partner. In addition, the virus initiating infection in individuals who were infected by someone other than their spouse was characterized to determine if genital infections mitigated the severe genetic bottleneck observed in a majority of epidemiologically linked heterosexual HIV-1 transmission events. In nearly 50% (3/7) of individuals infected by someone other than their spouse, multiple genetic variants from a single individual established infection. A statistically significant association was observed between infection by multiple genetic variants and an inflammatory genital infection in the newly infected individual. Thus, in the vast majority of HIV-1 transmission events in cohabiting heterosexual couples, a single genetic variant establishes infection. Nevertheless, this severe genetic bottleneck can be mitigated by the presence of inflammatory genital infections in the at risk partner, suggesting that this restriction on genetic diversity is imposed in large part by the mucosal barrier.
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http://dx.doi.org/10.1371/journal.ppat.1000274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2621345PMC
January 2009

What the better half is thinking: A comparison of men's and women's responses and agreement between spouses regarding reported sexual and reproductive behaviors in Rwanda.

Psychol Res Behav Manag 2009 10;2:47-58. Epub 2009 Mar 10.

Rwanda Zambia HIV Research Group, Emory University, Atlanta, Georgia, USA.

Objective: To compare responses to a sexual behavioral survey of spouses in cohabiting heterosexual relationships in Kigali, Rwanda.

Design: Cross-sectional survey.

Methods: Husbands and wives in 779 cohabiting couples were interviewed separately with parallel questionnaires. Participants were recruited from a three-year old cohort of 1458 antenatal clinic attendees enrolled in a prospective study in 1988. Analyses compared responses at the gender- and couple-level for agreement and disagreement.

Results: Couples were in disagreement more than agreement. Women reported occasionally refusing sex, suggesting condom use, and believing married men were unfaithful. Men reported being in a faithful relationship, greater condom use, and being understanding when wives refused sex. Agreement included relationship characteristics, safety of condoms, and whether condoms had ever been used in the relationship. Disagreement included the preferred timing of next pregnancy, desire for more children, and whether a birth control method was currently used and type of method.

Conclusions: Rwandan husbands and wives differed in sexual behavior and reproductive-related topics. Couple-level reporting provides the most reliable measure for relationship aspects as couples' agreement cannot be assumed among cohabiting partnerships. Furthermore, HIV prevention programs for couples should incorporate communication skills to encourage couple agreement of HIV-related issues.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218770PMC
http://dx.doi.org/10.2147/prbm.s4910DOI Listing
October 2012

Modified Kigali combined staging predicts risk of mortality in HIV-infected adults in Lusaka, Zambia.

AIDS Res Hum Retroviruses 2008 Jul;24(7):919-24

Division of Infectious Diseases, Emory University, Atlanta, Georgia 30030, USA.

We assessed the utility of the modified Kigali combined (MKC) staging system for predicting survival in HIV-infected Zambian adults in a prospective, longitudinal, open cohort. From 1995 to 2004, HIV-discordant couples (one HIV-infected partner and one HIV-negative partner) were recruited from couples' voluntary counseling and testing centers in Lusaka, Zambia and followed at 3-month intervals. MKC stage, which incorporates clinical stage with erythrocyte sedimentation rate (ESR), hematocrit, and body mass index (BMI), was determined at enrollment. Kaplan-Meier survival and Cox proportional hazard methods were used to calculate median survival and relative hazards. We enrolled 1479 HIV-discordant couples with a combined 7305 person-years of follow-up. Among HIV-infected participants over the 9-year study period, there were 333 confirmed deaths. The time to 50% mortality was 8.5 years with MKC stage 1 and 2 disease compared to 3.7 years with MKC stage 4 disease at enrollment. Survival rates at 3 years were 85% with MKC stage 1 and 2 disease, 74% with MKC stage 3 disease, and 51% with MKC stage 4 disease. A total of 275 HIV-negative partners seroconverted during follow-up. In comparison, survival rates at 3 years were 94% for HIV-negative participants and 92% for participants who seroconverted during follow-up. In multivariate analysis, MKC stage 4 disease (HR = 3.7, 95% CI = 2.7-5.0) remained a strong predictor of mortality. Incorporating ESR, hematocrit, and BMI with clinical staging is a powerful, low-cost tool to identify HIV-infected adults at high risk for mortality.
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http://dx.doi.org/10.1089/aid.2007.0297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928550PMC
July 2008

HIV-infected Rwandan women have a high frequency of long-term survival.

AIDS 2007 Nov;21 Suppl 6:S31-7

Division of HIV/AIDS Prevention, Centers for Disease Control andPrevention, 1600 Clifton Road N.E., MS E-45, Atlanta, GA 30030, USA.

Objectives: To evaluate rates of long-term survival in a prospective, longitudinal, closed HIV cohort in Africa between 1986 and 2006.

Methods: A total of 548 HIV-infected Rwandan women were recruited from prenatal clinics in Kigali and followed at 3-6 month intervals to February 2006. Overall, 401 women (73%) were HIV positive at initial cross-sectional testing in 1986 (seroprevalent cohort) and 147 women (27%) were initially HIV negative but seroconverted during follow-up from 1986 to 1993 (seroincident cohort). Kaplan-Meier survival methods were used to calculate survival times censored in mid-2003.

Results: In February 2006, 109 women (20%) remained alive in the cohort. Time to 50% non-genocide mortality was 11.9 years among seroincident women and 8.9 years among seroprevalent women. Smoothed mortality rates increased with duration of follow-up to a peak of 0.12 deaths per person-year at 9.5 years of follow-up but subsequently declined. After 15 years of follow-up (pre-HAART introduction), the survival probability was 36% for seroincident women and 26% for seroprevalent women. Most survivors had virological and immunological evidence of disease progression. The median CD4 cell count of survivors declined from 447 cells/mul in 1998 to 268 cells/mul in 2003. Among survivors, 57 women (52%) met treatment criteria and initiated antiretroviral treatment by 2006.

Conclusion: Although median survival times in this cohort were similar to those observed in high-income countries, the rates of long-term survival after 15 years of follow-up were higher than expected. A levelling off of mortality rates during the late stages of follow-up may explain this high rate of long-term survival.
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http://dx.doi.org/10.1097/01.aids.0000299408.52399.e1DOI Listing
November 2007

Access to adequate nutrition is a major potential obstacle to antiretroviral adherence among HIV-infected individuals in Rwanda.

AIDS 2006 Oct;20(16):2116-8

Emory University School of Medicine, Atlanta, Georgia, USA.

Despite the massive expansion of antiretroviral drugs in Africa, little is known about the resulting changes in sexual behavior or obstacles to antiretroviral therapy (ART) adherence. Our evaluation of Rwandan adults on ART found no increase in risky sexual behaviors, but an obstacle to ART initiation and adherence for 76% of patients was a fear of developing too much appetite without enough to eat. Access to adequate nutrition may be a major determinant for long-term adherence to ART.
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http://dx.doi.org/10.1097/01.aids.0000247580.16073.1bDOI Listing
October 2006

Transmission of HIV-1 and HLA-B allele-sharing within serodiscordant heterosexual Zambian couples.

Lancet 2004 Jun;363(9427):2137-9

Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294-0022, USA.

Factors that might increase risk of HIV-1 transmission include age, sex, and amount of HIV-1 RNA in plasma, but findings for HLA allele-sharing are not in agreement. We tested the hypothesis that allele sharing at HLA loci is associated with increased risk of transmission of HIV-1 infection in cohabiting heterosexual Zambian couples. We studied 125 initially serodiscordant partners with sequence-confirmed interpartner HIV-1 transmission and 104 couples who were persistently serodiscordant, and we analysed relations with molecularly typed HLA-A, B, and C alleles by survival techniques. After adjustment for other genetic and non-genetic risk factors seen with heterosexual transmission of HIV-1 in this cohort, sharing of HLA-B alleles was independently associated with accelerated intracouple transmission (relative hazard 2.23, 95% CI 1.52-3.26, p<0.0001). Selective pressure by HLA-B alleles on transmitted viruses accords with current understanding of the effect of B locus polymorphism in HIV-1 and perhaps other infections.
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http://dx.doi.org/10.1016/S0140-6736(04)16505-7DOI Listing
June 2004
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