Caprisa (Centre for the Aids programme of research in South Africa)

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Human immunodeficiency virus-specific gamma interferon enzyme-linked immunospot assay responses targeting specific regions of the proteome during primary subtype C infection are poor predictors of the course of viremia and set point.
(American Society for Microbiology., 2008) Gray, Clive M.; Mlotshwa, Mandla.; Riou, Catherine.; Mathebula, Tiyani.; Mashishi, Tumelo.; Seoighe, Cathal.; Ngandu, Nobubelo K.; de Assis Rosa, Debra.; van Loggerenberg, Francois.; Morris, Lynn.; Mlisana, Koleka Patience.; Williamson, Carolyn.; Abdool Karim, Salim Safurdeen.
It is unknown whether patterns of human immunodeficiency virus (HIV)-specific T-cell responses during acute infection may influence the viral set point and the course of disease. We wished to establish whether the magnitude and breadth of HIV type 1 (HIV-1)-specific T-cell responses at 3 months postinfection were correlated with the viral-load set point at 12 months and hypothesized that the magnitude and breadth of HIV-specific T-cell responses during primary infection would predict the set point. Gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses across the complete proteome were measured in 47 subtype C HIV-1-infected participants at a median of 12 weeks postinfection. When corrected for amino acid length and individuals responding to each region, the order of recognition was as follows: Nef > Gag > Pol > Rev > Vpr > Env > Vpu > Vif > Tat. Nef responses were significantly (P < 0.05) dominant, targeted six epitopic regions, and were unrelated to the course of viremia. There was no significant difference in the magnitude and breadth of responses for each protein region with disease progression, although there was a trend of increased breadth (mean, four to seven pools) in rapid progressors. Correlation of the magnitude and breadth of IFN-γ responses with the viral set point at 12 months revealed almost zero association for each protein region. Taken together, these data demonstrate that the magnitude and breadth of IFN-γ ELISPOT assay responses at 3 months postinfection are unrelated to the course of disease in the first year of infection and are not associated with, and have low predictive power for, the viral set point at 12 months.
Initial B-Cell responses to transmitted human immunodeficiency virus type 1: virion-binding immunoglobulin M (IgM) and IgG antibodies followed by plasma anti-gp41 antibodies with ineffective control of initial viremia.
(American Society for Microbiology., 2008) Tomaras, Georgia D.; Yates, Nicole L.; Liu, Pinghuang.; Qin, Li.; Fouda, Genevieve Giny.; Chavez, Leslie L.; Decamp, Allan C.; Parks, Robert J.; Ashley, Vicki C.; Lucas, Judith T.; Cohen, Myron S.; Eron, Joseph J.; Hick, Charles B.; Liao, Hua-Xin.; Self, Steven G.; Landucci, Gary.; Forthal, Donald N.; Weinhold, Kent J.; Keele, Brandon F.; Hahn, Beatrice H.; Greenberg, Michael L.; Morris, Lynn.; Abdool Karim, Salim Safurdeen.; Blattner, William A.; Montefiori, David Charles.; Shaw, George M.; Perelson, Alan S.; Haynes, Barton F.
A window of opportunity for immune responses to extinguish human immunodeficiency virus type 1 (HIV-1) exists from the moment of transmission through establishment of the latent pool of HIV-1-infected cells. A critical time to study the initial immune responses to the transmitted/founder virus is the eclipse phase of HIV-1 infection (time from transmission to the first appearance of plasma virus), but, to date, this period has been logistically difficult to analyze. To probe B-cell responses immediately following HIV-1 transmission, we have determined envelope-specific antibody responses to autologous and consensus Envs in plasma donors from the United States for whom frequent plasma samples were available at time points immediately before, during, and after HIV-1 plasma viral load (VL) ramp-up in acute infection, and we have modeled the antibody effect on the kinetics of plasma viremia. The first detectable B-cell response was in the form of immune complexes 8 days after plasma virus detection, whereas the first free plasma anti-HIV-1 antibody was to gp41 and appeared 13 days after the appearance of plasma virus. In contrast, envelope gp120-specific antibodies were delayed an additional 14 days. Mathematical modeling of the earliest viral dynamics was performed to determine the impact of antibody on HIV replication in vivo as assessed by plasma VL. Including the initial anti-gp41 immunoglobulin G (IgG), IgM, or both responses in the model did not significantly impact the early dynamics of plasma VL. These results demonstrate that the first IgM and IgG antibodies induced by transmitted HIV-1 are capable of binding virions but have little impact on acute-phase viremia at the timing and magnitude that they occur in natural infection.
The C3-V4 region is a major target of autologous neutralizing antibodies in human immunodeficiency virus type 1 subtype C Infection.
(American Society for Microbiology., 2008) Moore, Penelope L.; Gray, Elin Solomonovna.; Choge, Isaac Ang'Ang'A.; Ranchobe, Nthabeleng.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Morris, Lynn.
The early autologous neutralizing antibody response in human immunodeficiency virus type 1 (HIV-1) subtype C infections is often characterized by high titers, but the response is type specific with little to no cross-neutralizing activity. The specificities of these early neutralizing antibodies are not known; however, the type specificity suggests that they may target the variable regions of the envelope. Here, we show that cross-reactive anti-V3 antibodies developed within 3 to 12 weeks in six individuals but did not mediate autologous neutralization. Using a series of chimeric viruses, we found that antibodies directed at the V1V2, V4, and V5 regions contributed to autologous neutralization in some individuals, with V1V2 playing a more substantial role. However, these antibodies did not account for the total neutralizing capacity of these sera against the early autologous virus. Antibodies directed against the C3-V4 region were involved in autologous neutralization in all four sera studied. In two sera, transfer of the C3-V4 region rendered the chimera as sensitive to antibody neutralization as the parental virus. Although the C3 region, which contains the highly variable α2-helix was not a direct target in most cases, it contributed to the formation of neutralization epitopes as substitution of this region resulted in neutralization resistance. These data suggest that the C3 and V4 regions combine to form important structural motifs and that epitopes in this region are major targets of the early autologous neutralizing response in HIV-1 subtype C infection.
Fluidity of HIV-1-Specific T-Cell Responses during Acute and Early Subtype C HIV-1 Infection and Associations with Early Disease Progression.
(American Society for Microbiology, 2010) Mlotshwa, Mandla.; Riou, Catherine.; Chopera, Denis Rutendo.; de Assis Rosa, Debra.; Ntale, Roman.; Treurnicht, Florette K.; Woodman, Zenda.; Werner, Lise.; van Loggerenberg, Francois.; Mlisana, Koleka Patience.; Williamson, Carolyn.; Gray, Clive M.; Abdool Karim, Salim Safurdeen.
Deciphering immune events during early stages of human immunodeficiency virus type 1 (HIV-1) infection is critical for understanding the course of disease. We characterized the hierarchy of HIV-1-specific T-cell gamma interferon (IFN-y) enzyme-linked immunospot (ELISPOT) assay responses during acute subtype C infection in 53 individuals and associated temporal patterns of responses with disease progression in the first 12 months. There was a diverse pattern of T-cell recognition across the proteome, with the recognition of Nef being immunodominant as early as 3 weeks postinfection. Over the first 6 months, we found that there was a 23% chance of an increased response to Nef for every week postinfection (P = 0.0024), followed by a nonsignificant increase to Pol (4.6%) and Gag (3.2%). Responses to Env and regulatory proteins appeared to remain stable. Three temporal patterns of HIV-specific T-cell responses could be distinguished: persistent, lost, or new. The proportion of persistent T-cell responses was significantly lower (P = 0.0037) in individuals defined as rapid progressors than in those progressing slowly and who controlled viremia. Almost 90% of lost T-cell responses were coincidental with autologous viral epitope escape. Regression analysis between the time to fixed viral escape and lost T-cell responses (r = 0.61; P = 0.019) showed a mean delay of 14 weeks after viral escape. Collectively, T-cell epitope recognition is not a static event, and temporal patterns of IFN-y-based responses exist. This is due partly to viral sequence variation but also to the recognition of invariant viral epitopes that leads to waves of persistent T-cell immunity, which appears to associate with slower disease progression in the first year of infection.
HIV infection and tuberculosis in South Africa: an urgent need to escalate the public health response.
(Elsevier, 2009) Abdool Karim, Salim Safurdeen.; Churchyard, Gavin J.; Abdool Karim, Quarraisha.; Lawn, Stephen D.
One of the greatest challenges facing post-apartheid South Africa is the control of the concomitant HIV and tuberculosis epidemics. HIV continues to spread relentlessly, and tuberculosis has been declared a national emergency. In 2007, South Africa, with 0·7% of the world’s population, had 17% of the global burden of HIV infection, and one of the world’s worst tuberculosis epidemics, compounded by rising drug resistance and HIV co-infection. Until recently, the South African Government’s response to these diseases has been marked by denial, lack of political will, and poor implementation of policies and programmes. Nonetheless, there have been notable achievements in disease management, including substantial improvements in access to condoms, expansion of tuberculosis control efforts, and scale-up of free antiretroviral therapy (ART). Care for acutely ill AIDS patients and long-term provision of ART are two issues that dominate medical practice and the health-care system. Decisive action is needed to implement evidence-based priorities for the control of the HIV and tuberculosis epidemics. By use of the framework of the Strategic Plans for South Africa for tuberculosis and HIV/AIDS, we provide prioritised four-step approaches for tuberculosis control, HIV prevention, and HIV treatment. Strong leadership, political will, social mobilisation, adequate human and financial resources, and sustainable development of health-care services are needed for successful implementation of these approaches.
Limited Neutralizing Antibody Specificities Drive Neutralization Escape in Early HIV-1 Subtype C Infection.
(Plos, 2009) Moore, Penelope L.; Ranchobe, Nthabeleng.; Lambson, Bronwen Elizabeth.; Gray, Elin Solomonovna.; Cave, Eleanor.; Abrahams, Melissa-Rose.; Bandawe, Gama P.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Morris, Lynn.
We previously showed that HIV-1 subtype C viruses elicit potent but highly type-specific neutralizing antibodies (nAb) within the first year of infection. In order to determine the specificity and evolution of these autologous nAbs, we examined neutralization escape in four individuals whose responses against the earliest envelope differed in magnitude and potency. Neutralization escape occurred in all participants, with later viruses showing decreased sensitivity to contemporaneous sera, although they retained sensitivity to new nAb responses. Early nAb responses were very restricted, occurring sequentially and targeting only two regions of the envelope. In V1V2, limited amino acid changes often involving indels or glycans, mediated partial or complete escape, with nAbs targeting the V1V2 region directly in 2 cases. The alpha-2 helix of C3 was also a nAb target, with neutralization escape associated with changes to positively charged residues. In one individual, relatively high titers of anti-C3 nAbs were required to drive genetic escape, taking up to 7 weeks for the resistant variant to predominate. Thereafter titers waned but were still measurable. Development of this single anti-C3 nAb specificity was associated with a 7-fold drop in HIV-1 viral load and a 4-fold rebound as the escape mutation emerged. Overall, our data suggest the development of a very limited number of neutralizing antibody specificities during the early stages of HIV-1 subtype C infection, with temporal fluctuations in specificities as escape occurs. While the mechanism of neutralization escape appears to vary between individuals, the involvement of limited regions suggests there might be common vulnerabilities in the HIV-1 subtype C transmitted envelope.
Association of HIV-Specific and Total CD8+ T Memory Phenotypes in Subtype C HIV-1 Infection with Viral Set Point.
(The American Association of Immunologists, Inc., 2009) Burgers, Wendy A.; Riou, Catherine.; Mlotshwa, Mandla.; Maenetje, Pholo.; de Assis Rosa, Debra.; Brenchley, Jason.; Mlisana, Koleka Patience.; Douek, Daniel C.; Koup, Richard A.; Roederer, Mario.; De Bruyn, Guy.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Gray, Clive M.
Understanding early immunological events during HIV-1 infection that may set the course of disease progression is important for identifying correlates of viral control. This study explores the association of differentiation profiles of HIV-specific and total memory CD8+ T cells with viral set point. A cohort of 47 HIV-1-infected individuals, with differing viral set points at 12 mo, were recruited during acute infection. We identified that the magnitude of IFN-γ+ T cell responses at 6 mo postinfection did not associate with viral set point at 12 mo. A subset of 16 individuals was further studied to characterize CD8+ T cells for expression patterns of markers for memory differentiation, survival (CD127), senescence (CD57), and negative regulation (programmed death-1). We show that viral control and the predicted tempo of HIV disease progression in the first year of infection was associated with a synchronous differentiation of HIV-specific and total CD8+ memory subpopulations. At 6–9 mo postinfection, those with low viral set points had a significantly higher proportion of early differentiated HIV-specific and total memory CD8+ cells of a central memory (CD45RO+CD27+CCR7+) and intermediate memory (CD45RO−CD27+CCR7−) phenotype. Those with high viral set points possessed significantly larger frequencies of effector memory (CD45RO+CD27−CCR7−) cells. The proportions of memory subsets significantly correlated with CD38+CD8+ T cells. Thus, it is likely that a high Ag burden resulting in generalized immune activation may drive differentiation of HIV-specific and total memory CD8+ T cells.
Interleukin-10 Promoter Polymorphisms Influence HIV-1 Susceptibility and Primary HIV-1 Pathogenesis.
(The Infectious Diseases Society of America., 2008) Naicker, Dshanta Dyanedi.; Werner, Lise.; Kormuth, Emil.; Passmore, Jo-Ann Shelley.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Ndung'u, Peter Thumbi.
Interleukin (IL)–10 directly inhibits human immunodeficiency virus type 1 (HIV-1) replication, but it may also promote viral persistence by inactivation of effector immune mechanisms. Here, we show in an African cohort that individuals with genotypes associated with high IL-10 production at 2 promoter single-nucleotide polymorphisms ( 1082 and 592) were less likely to become HIV-1 infected but had significantly higher median plasma viral loads during the acute phase ( 3 months after infection). However, as the infection progressed, the association between genotype and median viral load was reversed. Thus, IL-10 may influence HIV-1 susceptibility and pathogenesis, but effects on the latter may differ according to the infection phase.
High titer HIV-1 V3-specific antibodies with broad reactivity but low neutralizing potency in acute infection and following vaccination.
(Elsevier, 2008) Davis, Katie L.; Gray, Elin Solomonovna.; Moore, Penelope L.; Decker, Julie M.; Salomon, Aidy.; Montefiori, David Charles.; Graham, Barney S.; Keefer, Michael C.; Pinter, Abraham.; Morris, Lynn.; Hahn, Beatrice H.; Shaw, George M.
Identifying the earliest neutralizing antibody specificities that are elicited following infection or vaccination by HIV-1 is an important objective of current HIV/AIDS vaccine research. We have shown previously that transplantation of HIV-1 V3 epitopes into an HIV-2 envelope (Env) scaffold provides a sensitive and specific means to detect and quantify HIV-1 V3 epitope specific neutralizing antibodies (Nabs) in human sera. Here, we employ this HIV-2/HIV-1 V3 scaffolding strategy to study the kinetics of development and breadth of V3- specific Nabs in longitudinal sera from individuals acutely infected with clade C or clade B HIV-1 and in human subjects immunized with clade B HIV-1 immunogens. HIV-2/HIV-1 chimeras containing V3 sequences matched to virus type (HIV-2 or HIV-1), subtype (clade B or C), or strain (autologous or heterologous) were used as test reagents. We found that by 3–8 weeks post infection, 12 of 14 clade C subjects had a median IC50 V3-specific Nab titer of 1:700 against chimeric viruses containing a heterologous clade C V3. By 5 months post-infection, all 14 subjects were positive for V3-specific Nabs with median titers of 1:8000 against heterologous clade C V3 and 1:1300 against clade B V3. Two acutely infected clade B patients developed heterologous clade B V3-specific Nabs at titers of 1:300 and 1:1800 by 13 weeks of infection and 1:5000 and 1:11000 by 7 months of infection. Titers were not different against chimeras containing autologous clade B V3 sequences. Each of 10 uninfected normal human volunteers who were immunized with clade B HIV-1 Env immunogens, but none of five sham immunized control subjects, developed V3-specific Nabs titers as high as 1:3000 (median 1:1300; range 1:700–1:3000). None of the HIV- 1 infected or vaccinated subjects had antibodies that neutralized primary HIV-1 virus strains. These results indicate that high-titer, broadly reactive V3-specific antibodies are among the first to be elicited during acute and early HIV-1 infection and following vaccination but these antibodies lack neutralizing potency against primary HIV-1 viruses, which effectively shield V3 from antibody binding to the functional Env trimer.
The challenge of discharging research ethics duties in resource-constrained settings.
(Plos, 2011) Singh, Jerome Amir.
No abstract available.
Recruitment of high risk women for HIV prevention trials: baseline HIV prevalence and sexual behavior in the CAPRISA 004 tenofovir gel trial.
(Biomed Central, 2010) Abdool Karim, Quarraisha.; Kharsany, Ayesha Bibi Mahomed.; Fröhlich, Janet Ann.; Baxter, Cheryl.; Yende Zuma, Nonhlanhla.; Mansoor, Leila Essop.; Mlisana, Koleka Patience.; Maarschalk, Silvia.; Arulappan, Natasha.; Grobler, Anna Christina.; Sibeko, Sengeziwe.; Omar, Zaheen.; Gengiah, Tanuja Narayansamy.; Mlotshwa, Mukelisiwe.; Samsunder, Natasha.; Abdool Karim, Salim Safurdeen.
Background: Young women in sub-Saharan Africa bear a disproportionate burden of HIV infection compared to men but have limited options to reduce their HIV risk. Microbicides could fill an important HIV prevention gap for sexually active women who are unable to successfully negotiate mutual monogamy or condom use. Purpose: This paper describes the baseline sample characteristics in the CAPRISA 004 trial which assessed the safety and effectiveness of the vaginal microbicide, 1% tenofovir gel for HIV prevention in South Africa. Methods: This analysis assessed the baseline demographic, clinical and sexual behavior data of women screened and enrolled into the trial. The characteristics were summarized using descriptive summary measures; expressed as means and percent for categorical variables. Results: HIV prevalence at screening was 25.8% [95% Confidence Interval (CI):23.9-27.7). Of the 889 eligibly enrolled women who contributed follow-up data, rural participants recruited from a family planning (FP) clinic were younger, more likely to be living apart from their regular partner, reported lower coital frequency, had lower condom use (p < 0.001). In contrast, urban participants recruited from a sexually transmitted disease (STD) clinic reported higher numbers of lifetime sexual partners, new partners in the last 30 days and receiving money in exchange for sex (p < 0.001). Conclusion: The populations selected provide suitable diverse target groups for HIV prevention intervention studies.
Potent and Broad Neutralization of HIV-1 Subtype C by Plasma Antibodies Targeting a Quaternary Epitope Including Residues in the V2 Loop.
(American Society for Microbiology., 2010) Moore, Penelope L.; Gray, Elin Solomonovna.; Sheward, Daniel J.; Madiga, Maphuti C.; Ranchobe, Nthabeleng.; Honnen, William J.; Nonyane, Molati.; Tumba, Nancy Lola.; Hermanus, Tandile.; Sibeko, Sengeziwe.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.; Pinter, Abraham.; Morris, Lynn.; Lai, Zhong.
The targets of broadly cross-neutralizing (BCN) antibodies are of great interest in the HIV vaccine field. We have identified a subtype C HIV-1-superinfected individual, CAP256, with high-level BCN activity, and characterized the antibody specificity mediating breadth. CAP256 developed potent BCN activity peaking at 3 years postinfection, neutralizing 32 (76%) of 42 heterologous viruses, with titers of antibodies against some viruses exceeding 1:10,000. CAP256 showed a subtype bias, preferentially neutralizing subtype C and A viruses over subtype B viruses. CAP256 BCN serum targeted a quaternary epitope which included the V1V2 region. Further mapping identified residues F159, N160, L165, R166, D167, K169, and K171 (forming the FN/LRD-K-K motif) in the V2 region as crucial to the CAP256 epitope. However, the fine specificity of the BCN response varied over time and, while consistently dependent on R166 and K169, became gradually less dependent on D167 and K171, possibly contributing to the incremental increase in breadth over 4 years. The presence of an intact FN/LRD-K-K motif in heterologous viruses was associated with sensitivity, although the length of the adjacent V1 loop modulated the degree of sensitivity, with a shorter V1 region significantly associated with higher titers. Repair of the FN/LRD-K-K motif in resistant heterologous viruses conferred sensitivity, with titers sometimes exceeding 1:10,000. Comparison of the CAP256 epitope with that of the PG9/PG16 monoclonal antibodies suggested that these epitopes overlapped, adding to the mounting evidence that this may represent a common neutralization target that should be further investigated as a potential vaccine candidate.
Safety and effectiveness of BufferGel and 0.5% PRO 2000 gel for the prevention of HIV infection in women.
(Lippincott Williams & Wilkins., 2010) Abdool Karim, Salim Safurdeen.; Richardson, Barbra Ann.; Ramjee, Gita.; Hoffman, Irving F.; Chirenje, Zvavahera Mike.; Taha, Taha E.; Kapina, Muzala.; Maslankowski, Lisa.; Coletti, Anne S.; Profy, Albert.; Moench, Thomas R.; Piwowar-Manning, Estelle.; Masse, Benoit.; Hillier, Sharon Louise.; Soto-Torres, Lydia.
Objective: To determine the safety and effectiveness of BufferGel and 0.5% PRO2000 microbicide gels for the prevention of male-to-female HIV transmission. Design: Phase II/IIb, randomized, placebo-controlled trial with three double-blinded gel arms and an open-label no gel arm. Methods: Study participants from Malawi, South Africa, Zambia, Zimbabwe, and the USA were instructed to apply study gel up to 1 h before each sex act and safety, sexual behavior, pregnancy, gel adherence, acceptability, and HIV serostatus were assessed during follow-up. Results: The 3101 enrolled women were followed for an average of 20.4 months with 93.6% retention and 81.1% self-reported gel adherence. Adverse event rates were similar in all study arms. HIV incidence rates in the 0.5% PRO2000 gel, BufferGel, placebo gel, and no gel arms were 2.70, 4.14, 3.91, and 4.02 per 100 women-years, respectively. HIV incidence in the 0.5% PRO2000 gel arm was lower than the placebo gel arm (hazard ratio = 0.7, P=0.10) and the no gel arm (hazard ratio = 0.67, P=0.06). HIV incidence rates were similar in the BufferGel and both placebo gel (hazard ratio =1.10, P=0.63) and no gel control arms (hazard ratio =1.05, P=0.78). HIV incidence was similar in the placebo gel and no gel arms (hazard ratio =0.97, P=0.89). Conclusion: The 0.5% PRO2000 gel demonstrated a modest 30% reduction in HIV acquisition in women. However, these results were not statistically significant and subsequent findings from the Microbicide Development Programme (MDP) 301 trial have confirmed that 0.5% PRO2000 gel has little or no protective effect. BufferGel did not alter the risk of HIV infection. Both products were well tolerated.
Initiating antiretrovirals during tuberculosis treatment: a drug safety review.
(Informa UK, Ltd., 2011) Gengiah, Tanuja Narayansamy.; Gray, Andrew Lofts.; Naidoo, Kogieleum.; Abdool Karim, Quarraisha.
Introduction: Integrating HIV and tuberculosis (TB) treatment can reduce mortality substantially. Practical barriers to treatment integration still exist and include safety concerns related to concomitant drug use because of drug interactions and additive toxicities. Altered therapeutic concentrations may influence the chances of treatment success or toxicity. Areas covered: The available data on drug--drug interactions between the rifamycin class of anti-mycobacterials and the non-nucleoside reverse transcriptase inhibitor and the protease inhibitor classes of antiretrovirals are discussed with recommendations for integrated use. Additive drug toxicities, the impact of immune reconstitution inflammatory syndrome (IRIS) and the latest data on survival benefits of integrating treatment are elucidated. Expert opinion: Deferring treatment of HIV to avoid drug interactions with TB treatment or the occurrence of IRIS is not necessary. In the integrated management of TB--HIV co-infection, rational drug combinations aimed at reducing toxicities while effecting TB cure and suppressing HIV viral load are possible.
Virological and Immunological Factors Associated with HIV-1 Differential Disease Progression in HLA-B*58:01-Positive Individuals.
(American Society for Microbiology., 2010) Chopera, Denis Rutendo.; Mlotshwa, Mandla.; Woodman, Zenda.; Mlisana, Koleka Patience.; de Assis Rosa, Debra.; Martin, Darren Patrick.; Abdool Karim, Salim Safurdeen.; Gray, Clive M.; Williamson, Carolyn.
Molecular epidemiology studies have identified HLA-B*58:01 as a protective HIV allele. However, not all B*58:01-expressing persons exhibit slow HIV disease progression. We followed six HLA-B*58:01-positive, HIV subtype C-infected individuals for up to 31 months from the onset of infection and observed substantial variability in their clinical progression despite comparable total breadths of T cell responses. We therefore investigated additional immunological and virological factors that could explain their different disease trajectories. Cytotoxic T-lymphocyte (CTL) responses during acute infection predominantly targeted the TW10 and KF9 epitopes in p24Gag and Nef, respectively. Failure to target the TW10 epitope in one B*58:01-positive individual was associated with low CD4 counts and rapid disease progression. Among those targeting TW10, escape mutations arose within 2 to 15 weeks of infection. Rapid escape was associated with preexisting compensatory mutations in the transmitted viruses, which were present at a high frequency (69%) in the study population. At 1 year post infection, B*58:01-positive individuals who targeted and developed escape mutations in the TW10 epitope (n=5) retained significantly higher CD4 counts (P=0.04), but not lower viral loads, than non-B*58:01-positive individuals (n=17). The high population-level frequency of these compensatory mutations may be limiting the protective effect of the B*58:01 allele.
Association of TRIM22 with the Type 1 Interferon Response and Viral Control during Primary HIV-1 Infection.
(American Society for Microbiology., 2010) Singh, Ravesh.; Gaiha, Gaurav.; Werner, Lise.; Mlisana, Koleka Patience.; Luban, Jeremy.; Walker, Bruce D.; Abdool Karim, Salim Safurdeen.; Ndung'u, Peter Thumbi.; Brass, Abraham.; McKim, Kevin.
Type 1 interferons (IFNs) induce the expression of the tripartite interaction motif (TRIM) family of E3 ligases, but the contribution of these antiviral factors to HIV pathogenesis is not completely understood. We hypothesized that the increased expression of select type 1 IFN and TRIM isoforms is associated with a significantly lower likelihood of HIV-1 acquisition and viral control during primary HIV-1 infection. We measured IFN-a, IFN-b, myxovirus resistance protein A (MxA), human TRIM5a (huTRIM5a), and TRIM22 mRNA levels in peripheral blood mononuclear cells (PBMCs) of high-risk, HIV-1-uninfected participants and HIV-1-positive study participants. Samples were available for 32 uninfected subjects and 28 infected persons, all within 1 year of infection. HIV-1-positive participants had higher levels of IFN-b(P=0.0005), MxA (P=0.007), and TRIM22 (P=0.01) and lower levels of huTRIM5a (P< 0.001) than did HIV-1-negative participants. TRIM22 but not huTRIM5a correlated positively with type 1 IFN (IFN-a, IFN-b, and MxA) (all P<0.0001). In a multivariate model, increased MxA expression showed a significant positive association with viral load (P=0.0418). Furthermore, TRIM22 but not huTRIM5a, IFN-a, IFN-b, or MxA showed a negative correlation with plasma viral load (P=0.0307) and a positive correlation with CD4 T-cell counts (P=0.0281). In vitro studies revealed that HIV infection induced TRIM22 expression in PBMCs obtained from HIV-negative donors. Stable TRIM22 knockdown resulted in increased HIV-1 particle release and replication in Jurkat reporter cells. Collectively, these data suggest concordance between type 1 IFN and TRIM22 but not huTRIM5a expression in PBMCs and that TRIM22 likely acts as an antiviral effector in vivo.
Association of polymorphisms in the LEDGF/p75 gene (PSIP1) with susceptibility to HIV-1 infection and disease progression.
(Lippincott Williams & Wilkins., 2011) Madlala, Paradise Zamokuhle.; Gijsbers, Rik.; Christ, Frauke.; Hombrouck, Anneleen.; Werner, Lise.; Mlisana, Koleka Patience.; An, Ping.; Abdool Karim, Salim Safurdeen.; Winkler, Cheryl Ann.; Debyser, Zeger.; Ndung'u, Peter Thumbi.
Objective: LEDGF/p75, encoded by the PSIP1 gene, interacts with HIV-1 integrase and targets HIV-1 integration into active genes. We investigated the influence of polymorphisms in PSIP1 on HIV-1 acquisition and disease progression in black South Africans. Methods: Integrase binding domain of LEDGF/p75 was sequenced in 126 participants. Four haplotype tagging SNPs rs2277191, rs1033056, rs12339417 and rs10283923 referred to as SNP1, SNP2, SNP3 and SNP4, respectively, and one exonic SNP rs61744944 (SNP5, Q472L) were genotyped in 195 HIV-1 seronegative, 52 primary and 403 chronically infected individuals using TaqMan assays. LEDGF/p75 expression was quantified by real-time RT-PCR. The impact of Q472L mutation on the interaction with HIV_1 IN was measured by AlphaScreen. Results: rs2277191 (SNP1) A was more frequent among seropositives (P=0.06, Fisher’s exact test). Among individuals followed longitudinally SNP1A trended towards association with higher likelihood of HIV-1 acquisition [relative hazard (RH)=2.21, P=0.08; Cox model] and it was also associated with rapid disease progression (RH=5.98, P=0.04; Cox model) in the recently infected (primary infection) cohort. rs12339417 (SNP3)C was associated with slower decline of CD4+ T cells (P=0.02) and lower messenger RNA (mRNA) levels of LEDGF/p75 (P<0.01). Seroconverters had higher preinfection mRNA levels of LEDGF/p75 (P<0.01) and these levels decreased after HIV-1 infection (P=0.02). Conclusions: Genetic variants of PSIP1 may affect HIV-1 outcomes. Further studies are needed to confirm the effect of genetic variation of PSIP1 on HIV-1 pathogenesis in different cohorts.
Antiretroviral prophylaxis: a defining moment in HIV control.
(Elsevier., 2011) Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.
No abstract available.
Duffy-Null–Associated Low Neutrophil Counts Influence HIV-1 Susceptibility in High-Risk South African Black Women.
(Oxford University Press., 2010) Ramsuran, Veron.; Kulkarni, Hemant.; He, Weijing.; Mlisana, Koleka Patience.; Wright, Edwina J.; Werner, Lise.; Castiblanco, John.; Dhanda, Rahul.; Le, Tuan.; Dolan, Matthew J.; Guan, Weihua.; Weiss, Robin A.; Clark, Robert A.; Abdool Karim, Salim Safurdeen.; Ahuja, Sunil K.; Ndung'u, Peter Thumbi.
Background. The Duffy-null trait and ethnic netropenia are both highly prevalent in Africa. The influence of pre-seroconversion levels of peripheral blood cell counts (PBCs) on the risk of acquiring human immunodeficiency virus (HIV)–1 infection among Africans is unknown. Methods. The triangular relationship among pre-seroconversion PBC counts, host genotypes, and risk of HIV acquisition was determined in a prospective cohort of black South African high-risk female sex workers. Twenty seven women had seroconversion during follow-up, and 115 remained HIV negative for 2 years, despite engaging in high-risk activity. Results. Pre-seroconversion neutrophil counts in women who subsequently had seroconversion were significantly lower, whereas platelet counts were higher, compared with those who remained HIV negative. Comprising 27% of the cohort, subjects with pre-seroconversion neutrophil counts of <2500 cells/mm3 had a ~3-fold greater risk of acquiring HIV infection. In a genome-wide association analyses, an African-specific polymorphism (rs2814778) in the promoter of Duffy Antigen Receptor for Chemokines (DARC -46T>C) was significantly associated with neutrophil counts (P = 7.9 x10-11). DARC -46C/C results in loss of DARC expression on erthyrocytes (Duffy-null) and resistance to Plasmodium vivax malaria, and in our cohort, only subjects with this genotype had pre-seroconversion neutrophil counts of <2500 cells/mm3. The risk of acquiring HIV infection was ~3-fold greater in those with the trait of Duffy-null–associated low neutrophil counts, compared with all other study participants. Conclusions. Pre-seroconversion neutrophil and platelet counts influence risk of HIV infection. The trait of Duffy-null–associated low neutrophil counts influences HIV susceptibility. Because of the high prevalence of this trait among persons of African ancestry, it may contribute to the dynamics of the HIV epidemic in Africa.
Time for gender mainstreaming in editorial policies.
(International AIDS Society., 2011) Heidari, Shirin.; Eckert, Mirjam J.; Kippax, Susan.; Abdool Karim, Quarraisha.; Sow, Papa Salif.; Wainberg, Mark A.
The HIV epidemic has been continuously growing among women, and in some parts of the world, HIV-infected women outnumber men. Women’s greater vulnerability to HIV, both biologically and socially, influences their health risk and health outcome. This disparity between sexes has been established for other diseases, for example, autoimmune diseases, malignancies and cardiovascular diseases. Differences in drug effects and treatment outcomes have also been demonstrated. Despite proven sex and gender differences, women continue to be underrepresented in clinical trials, and the absence of gender analyses in published literature is striking. There is a growing advocacy for consideration of women in research, in particular in the HIV field, and gender mainstreaming of policies is increasingly called for. However, these efforts have not translated into improved reporting of sex-disaggregated data and provision of gender analysis in published literature; science editors, as well as publishers, lag behind in this effort. Instructions for authors issued by journals contain many guidelines for good standards of reporting, and a policy on sex-disaggregated data and gender analysis should not be amiss here. It is time for editors and publishers to demonstrate leadership in changing the paradigm in the world of scientific publication. We encourage authors, peer reviewers and fellow editors to lend their support by taking necessary measures to substantially improve reporting of gender analysis. Editors’ associations could play an essential role in facilitating a transition to improved standard editorial policies.

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