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

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Adaptive changes in HIV-1 subtype C proteins during early infection are driven by changes in HLA-associated immune pressure.
(Elsevier., 2009) Treurnicht, Florette K.; Seoighe, Cathal.; Martin, Darren Patrick.; Wood, N.; Abrahams, Melissa-Rose.; de Assis Rosa, Debra.; Bredell, Helba.; Woodman, Zenda.; Hide, Winston.; Mlisana, Koleka Patience.; Abdool Karim, Salim Safurdeen.; Gray, Clive M.; Williamson, Carolyn.
It is unresolved whether recently transmitted human immunodeficiency viruses (HIV) have genetic features that specifically favour their transmissibility. To identify potential “transmission signatures”, we compared 20 full-length HIV-1 subtype C genomes from primary infections, with 66 sampled from ethnically and geographically matched individuals with chronic infections. Controlling for recombination and phylogenetic relatedness, we identified 39 sites at which amino acid frequency spectra differed significantly between groups. These sites were predominantly located within Env, Pol and Gag (14/39, 9/39 and 6/39 respectively) and were significantly clustered (33/39) within known immunoreactive peptides. Within 6 months of infection, we detected reversion-to-consensus mutations at 14 sites and potential CTL escape mutations at seven. Here we provide evidence that frequent reversion mutations probably allows the virus to recover replicative fitness which, together with immune escape driven by the HLA alleles of the new hosts, differentiate sequences from chronic infections from those sampled shortly after transmission.
CAPRISA 004 tenofovir microbicide trial: no impact of tenofovir gel on the HIV transmission bottleneck.
(Oxford University Press., 2011) Valley-Omar, Ziyaad.; Sibeko, Sengeziwe.; Anderson, Jeffrey A.; Goodier, Sarah A.; Werner, Lise.; Arney, Leslie.; Naranbhai, Vivek.; Treurnicht, Florette K.; Abrahams, Melissa-Rose.; Bandawe, Gama P.; Swanstrom, Ronald.; Abdool Karim, Salim Safurdeen.; Abdool Karim, Quarraisha.; Williamson, Carolyn.
Alterations of the genital mucosal barrier may influence the number of viruses transmitted from a human immunodeficiency virus–infected source host to the newly infected individual. We used heteroduplex tracking assay and single-genome sequencing to investigate the effect of a tenofovir-based microbicide gel on the transmission bottleneck in women who seroconverted during the CAPRISA 004 microbicide trial. Seventy-seven percent (17 of 22; 95% confidence interval [CI], 56%–90%) of women in the tenofovir gel arm were infected with a single virus compared with 92% (13 of 14; 95% CI, 67%–>99%) in the placebo arm (P = .37). Tenofovir gel had no discernable impact on the transmission bottleneck.
Case report: mechanisms of HIV elite control in two African women.
(BioMed Central., 2018) Moosa, Yumna.; Tanko, Ramla F.; Ramsuran, Veron.; Singh, Ravesh.; Madzivhandila, Mashudu.; Yende-Zuma, Fortunate Nonhlanhla.; Abrahams, Melissa-Rose.; Selhorst, Philippe.; Gounder, Kamini.; Moore, Penelope L.; Williamson, Carolyn.; Abdool Karim, Salim Safurdeen.; Garrett, Nigel Joel.; Burgers, Wendy A.
Abstract available in pdf.
Comparison of viral env proteins from acute and chronic infections with subtype C human immunodeficiency virus type 1 identifies differences in glycosylation and CCR5 utilization and suggests a new strategy for immunogen design.
(American Society for Microbiology., 2013) Ping, Li-Hua.; Joseph, Sarah B.; Anderson, Jeffrey A.; Abrahams, Melissa-Rose.; Salazar-Gonzalez, Jesus F.; Kincer, Laura P.; Treurnicht, Florette K.; Arney, Leslie.; Ojeda, Suany.; Zhang, Ming.; Keys, Jessica.; Potter, E. Lake.; Chu, Haitao.; Moore, Penelope L.; Salazar-Gonzalez, Maria.; Iyer, Shilpa.; Jabara, Cassandra.; Kirchherr, Jennifer.; Mapanje, Clement.; Ngandu, Nobubelo K.; Seoighe, Cathal.; Hoffman, Irving F.; Gao, Feng.; Tang, Yuyang.; Labranche, Celia.; Lee, Benhur.; Saville, Andrew.; Vermeulen, Marion.; Fiscus, Susan A.; Morris, Lynn.; Abdool Karim, Salim Safurdeen.; Haynes, Barton F.; Shaw, George M.; Korber, Bette T. M.; Hahn, Beatrice H.; Cohen, Myron S.; Montefiori, David Charles.; Williamson, Carolyn.; Swanstrom, Ronald.
Understanding human immunodeficiency virus type 1 (HIV-1) transmission is central to developing effective prevention strategies, including a vaccine.We compared phenotypic and genetic variation in HIV-1 env genes from subjects in acute/early infection and subjects with chronic infections in the context of subtype C heterosexual transmission.We found that the transmitted viruses all used CCR5 and required high levels of CD4 to infect target cells, suggesting selection for replication in T cells and not macrophages after transmission. In addition, the transmitted viruses were more likely to use a maraviroc-sensitive conformation of CCR5, perhaps identifying a feature of the target T cell.We confirmed an earlier observation that the transmitted viruses were, on average, modestly under-glycosylated relative to the viruses from chronically infected subjects. This difference was most pronounced in comparing the viruses in acutely infected men to those in chronically infected women. These features of the transmitted virus point to selective pressures during the transmission event.We did not observe a consistent difference either in heterologous neutralization sensitivity or in sensitivity to soluble CD4 between the two groups, suggesting similar conformations between viruses from acute and chronic infection. However, the presence or absence of glycosylation sites had differential effects on neutralization sensitivity for different antibodies.We suggest that the occasional absence of glycosylation sites encoded in the conserved regions of env, further reduced in transmitted viruses, could expose specific surface structures on the protein as antibody targets.
Decreased incidence of dual infections in South African subtype C-infected women compared to a cohort ten years earlier.
(Mary Ann Liebert., 2011) Woodman, Zenda.; Mlisana, Koleka Patience.; Treurnicht, Florette K.; Abrahams, Melissa-Rose.; Thebus, Ruwayhida.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.
Previously, we determined the incidence of dual infections in a South African cohort and its association with higher viral setpoint. Ten years later, we compare the incidence and impact of dual infections at transmission on viral setpoint in a geographically similar cohort (n=46) making use of both the heteroduplex mobility assay (HMA) and the more recent single genome amplification (SGA) approach. HIV incidence was lower in this cohort (7% compared to 18%), and we find a similar reduction in the number of dual infections (9% compared to 19%). Unlike the previous study, there was no association between either dual infection (n=4) or multivariant transmission (n=7) and disease progression. This study emphasized the importance of monitoring changes in the HIV epidemic as it may have important ramifications on our understanding of the natural history of disease.
Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escape.
(Nature Publishing Group., 2012) Moore, Penelope L.; Gray, Elin Solomonovna.; Wibmer, Constantinos Kurt.; Bhiman, Jinal N.; Nonyane, Molati.; Hermanus, Tandile.; Sheward, Daniel J.; Bajimaya, Shringkhala.; Abrahams, Melissa-Rose.; Tumba, Nancy Lola.; Ping, Li-Hua.; Ngandu, Nobubelo K.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Swanstrom, Ronald.; Seaman, Michael S.; Williamson, Carolyn.; Morris, Lynn.;
Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful, a minority of individuals naturally develop these antibodies after many years of infection. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1–infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes.
Genital tract inflammation during early HIV-infection predicts higher plasma viral load set point in women.
(Oxford University Press., 2011) Roberts, Lindi.; Passmore, Jo-Ann Shelley.; Mlisana, Koleka Patience.; Williamson, Carolyn.; Little, Francesca.; Bebell, Lisa M.; Walzl, Gerhard.; Abrahams, Melissa-Rose.; Woodman, Zenda.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.
Background. The biggest challenge in human immunodeficiency virus type 1 (HIV-1) prevention in Africa is the high HIV-1 burden in young women. In macaques, proinflammatory cytokine production in the genital tract is necessary for target cell recruitment and establishment of simian immunodeficiency virus (SIV) infection following vaginal inoculation. The purpose of this study was to assess if genital inflammation during early HIV-1 infection predisposes women to rapid disease progression. Methods. Inflammatory cytokine concentrations were measured in cervicovaginal lavage (CVL) from 49 women 6, 17, 30, and 55 weeks after HIV-1 infection and from 22 of these women before infection. Associations between genital inflammation and viral load set point and blood CD4 cell counts 12 months after infection were investigated. Results. Elevated genital cytokine concentrations 6 and 17 weeks after HIV-1 infection were associated with higher viral load set points and, to a lesser extent, with CD4 depletion. CVL cytokine concentrations during early infection did not differ relative to preinfection but were elevated in women who had vaginal discharge, detectable HIV-1 RNA in their genital tracts, and lower blood CD4 counts. Conclusion. Genital inflammation during early HIV-1 infection was associated with higher viral load set point and CD4 depletion, which are markers of rapid disease progression. Strategies aimed at reducing genital inflammation during early HIV-1 infection may slow disease progression.
Increased memory differentiation is associated with decreased polyfunctionality for HIV but not for CMV-specific CD8+ T cells.
(American Association of Immunologists., 2012) Riou, Catherine.; Treurnicht, Florette K.; Abrahams, Melissa-Rose.; Mlisana, Koleka Patience.; Liu, Michael K. P.; Goonetilleke, Nilu.; Koup, Richard A.; Roederer, Mario.; Abdool Karim, Salim Safurdeen.; De Bruyn, Guy.; Williamson, Carolyn.; Gray, Clive M.; Burgers, Wendy A.
The generation of polyfunctional CD8+ T cells, in response to vaccination or natural infection, has been associated with improved protective immunity. However, it is unclear whether the maintenance of polyfunctionality is related to particular cellular phenotypic characteristics. To determine whether the cytokine expression profile is linked to the memory differentiation stage, we analyzed the degree of polyfunctionality of HIV-specific CD8+ T cells within different memory subpopulations in 20 antiretroviral therapy-naive HIV-1–infected individuals at ∼34 wk postinfection. These profiles were compared with CMV-specific CD8+ T cell responses in HIV-uninfected control subjects and in individuals chronically infected with HIV. Our results showed that the polyfunctional abilities of HIV-specific CD8+ T cells differed according to their memory phenotype. Early-differentiated cells (CD45RO+CD27+) exhibited a higher proportion of cells positive for three or four functions (p < 0.001), and a lower proportion of monofunctional cells (p < 0.001) compared with terminally differentiated (TD; CD45RO-CD27-) HIV-specific CD8+ T cells. The majority of TD HIV-specific CD8+ T cells were monofunctional (median 69% [interquartile range: 57–83]), producing predominantly CD107a or MIP1b. Moreover, proportions of HIV-specific monofunctional CD8+ T cells positively associated with proportions of TD HIV-specific CD8+ T cells (p = 0.019, r = 0.54). In contrast, CMV-specific CD8+ T cell polyfunctional capacities were similar across all memory subpopulations, with terminally and early-differentiated cells endowed with comparable polyfunctionality. Overall, these data show that the polyfunctional abilities of HIV-specific CD8+ T cells are influenced by the stage of memory differentiation, which is not the case for CMV-specific responses.
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.
Quantitating the multiplicity of infection with human immunodeficiency virus type 1 subtype C reveals a non-poisson distribution of transmitted variants.
(American Society for Microbiology., 2008) Abrahams, Melissa-Rose.; Anderson, Jeffrey A.; Giorgi, Elena E.; Seoighe, Cathal.; Mlisana, Koleka Patience.; Liu, Pinghuang.; Athreya, G. S.; Treurnicht, Florette K.; Keele, Brandon F.; Wood, N.; Salazar-Gonzalez, Jesus F.; Bhattacharya, Tanmoy.; Chu, Haitao.; Hoffman, Irving F.; Galvin, S.; Mapanje, Clement.; Kazembe, P.; Thebus, Ruwayhida.; Fiscus, Susan A.; Hide, Winston.; Cohen, Myron S.; Abdool Karim, Salim Safurdeen.; Haynes, Barton F.; Shaw, George M.; Hahn, Beatrice H.; Korber, Bette T. M.; Swanstrom, Ronald.; Williamson, Carolyn.
Identifying the specific genetic characteristics of successfully transmitted variants may prove central to the development of effective vaccine and microbicide interventions. Although human immunodeficiency virus transmission is associated with a population bottleneck, the extent to which different factors influence the diversity of transmitted viruses is unclear. We estimate here the number of transmitted variants in 69 heterosexual men and women with primary subtype C infections. From 1,505 env sequences obtained using a single genome amplification approach we show that 78% of infections involved single variant transmission and 22% involved multiple variant transmissions (median of 3). We found evidence for mutations selected for cytotoxic-T-lymphocyte or antibody escape and a high prevalence of recombination in individuals infected with multiple variants representing another potential escape pathway in these individuals. In a combined analysis of 171 subtype B and C transmission events, we found that infection with more than one variant does not follow a Poisson distribution, indicating that transmission of individual virions cannot be seen as independent events, each occurring with low probability. While most transmissions resulted from a single infectious unit, multiple variant transmissions represent a significant fraction of transmission events, suggesting that there may be important mechanistic differences between these groups that are not yet understood.
Rapid, complex adaption of transmitted HIV-1 full-length genomes in subtype C-infected individuals with differing disease progression.
(Wolters Kluwer Health., 2013) Abrahams, Melissa-Rose.; Treurnicht, Florette K.; Ngandu, Nobubelo K.; Goodier, Sarah A.; Marais, Jinny C.; Bredell, Helba.; Thebus, Ruwayhida.; de Assis Rosa, Debra.; Seoighe, Cathal.; Abdool Karim, Salim Safurdeen.; Gray, Clive M.; Williamson, Carolyn.; Mlisana, Koleka Patience.
Objective(s): There is limited information on full-length genome sequences and the early evolution of transmitted HIV-1 subtype C viruses, which constitute the majority of viruses spread in Africa. The purpose of this study was to characterize the earliest changes across the genome of subtype C viruses following transmission, to better understand early control of viremia. Design: We derived the near full-length genome sequence responsible for clinical infection from five HIV subtype C-infected individuals with different disease progression profiles and tracked adaptation to immune responses in the first 6 months of infection. Methods: Near full-length genomes were generated by single genome amplification and direct sequencing. Sequences were analyzed for amino acid mutations associated with cytotoxic T lymphocyte (CTL) or antibody-mediated immune pressure, and for reversion. Results: Fifty-five sequence changes associated with adaptation to the new host were identified, with 38% attributed to CTL pressure, 35% to antibody pressure, 16% to reversions and the remainder were unclassified. Mutations in CTL epitopes were most frequent in the first 5 weeks of infection, with the frequency declining over time with the decline in viral load. CTL escape predominantly occurred in nef, followed by pol and env. Shuffling/toggling of mutations was identified in 81% of CTL epitopes, with only 7% reaching fixation within the 6-month period. Conclusion: There was rapid virus adaptation following transmission, predominantly driven by CTL pressure, with most changes occurring during high viremia. Rapid escape and complex escape pathways provide further challenges for vaccine protection.
Replication capacity of viruses from acute infection drives HIV-1 disease progression.
(American Society for Microbiology., 2017) Selhorst, Philippe.; Combrinck, Carina.; Ndabambi, Nonkululeko.; Ismail, Sherazaan D.; Abrahams, Melissa-Rose.; Lacerda, Miguel.; Samsunder, Natasha.; Garrett, Nigel Joel.; Abdool Karim, Quarraisha.; Abdool Karim, Salim Safurdeen.; Williamson, Carolyn.
Abstract available in pdf.
Vertical T cell immunodominance and epitope entropy determine HIV-1 escape.
(American Society for Clinical Investigation., 2012) Liu, Michael K. P.; Hawkins, Natalie.; Ritchie, Adam J.; Ganusov, Vitaly.; Whale, Victoria.; Brackenridge, Simon.; Li, Hui.; Pavlicek, Jeffrey W.; Cai, Fangping.; Abrahams, Melissa-Rose.; Treurnicht, Florette K.; Hraber, Peter.; Riou, Catherine.; Gray, Clive M.; Ferrari, Guido.; Tanner, Rachel.; Ping, Li-Hua.; Anderson, Jeffrey A.; Swanstrom, Ronald.; Cohen, Myron S.; Abdool Karim, Salim Safurdeen.; Haynes, Barton F.; Borrow, Persephone.; Perelson, Alan S.; Shaw, George M.; Hahn, Beatrice H.; Williamson, Carolyn.; Korber, Bette T. M.; Gao, Feng.; Self, Steven G.; McMichael, Andrew.; Goonetilleke, Nilu.
HIV-1 accumulates mutations in and around reactive epitopes to escape recognition and killing by CD8+ T cells. Measurements of HIV-1 time to escape should therefore provide information on which parameters are most important for T cell–mediated in vivo control of HIV-1. Primary HIV-1–specific T cell responses were fully mapped in 17 individuals, and the time to virus escape, which ranged from days to years, was measured for each epitope. While higher magnitude of an individual T cell response was associated with more rapid escape, the most significant T cell measure was its relative immunodominance measured in acute infection. This identified subject-level or “vertical” immunodominance as the primary determinant of in vivo CD8+ T cell pressure in HIV-1 infection. Conversely, escape was slowed significantly by lower population variability, or entropy, of the epitope targeted. Immunodominance and epitope entropy combined to explain half of all the variability in time to escape. These data explain how CD8+ T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV-1 escape should be considered in the context of immunodominance.

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