Browsing by Author "Karim, Salim Abdool"

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    Open Access
    Features of recently transmitted HIV-1 clade C viruses that impact antibody recognition: implications for active and passive immunization
    (Public Library of Science, 2016) Rademeyer, Cecilia; Korber, Bette; Seaman, Michael S; Giorgi, Elena E; Thebus, Ruwayhida; Robles, Alexander; Sheward, Daniel J; Wagh, Kshitij; Garrity, Jetta; Carey, Brittany R; Gao, Hongmei; Greene, Kelli M; Tang, Haili; Bandawe, Gama P; Marais, Jinny C; Diphoko, Thabo E; Hraber, Peter; Tumba, Nancy; Moore, Penny L; Gray, Glenda E; Kublin, James; McElrath, M Juliana; Vermeulen, Marion; Middelkoop, Keren; Bekker, Linda-Gail; Hoelscher, Michael; Maboko, Leonard; Makhema, Joseph; Robb, Merlin L; Karim, Salim Abdool; Karim, Quarraisha Abdool; Kim, Jerome H; Hahn, Beatrice H; Gao, Feng; Swanstrom, Ronald; Morris, Lynn; Montefiori, David C; Williamson, Carolyn
    Author Summary: Vaccine and passive immunization prophylactic trials that rely on antibody-mediated protection are planned for HIV-1 clade C epidemic regions of southern Africa, which have amongst the highest HIV-1 incidences globally. This includes a phase 2b trial of passively administered monoclonal antibody, VRC01; as well as a phase 3 trial using the clade C modified version of the partially efficacious RV144 vaccine. The extraordinary diversity of HIV-1 poses a major obstacle to these interventions, and our study aimed to determine the implications of viral diversity on antibody recognition. Investigations using our panel of very early viruses augment current knowledge of vulnerable targets on transmitted viruses for vaccine design and passive immunization studies. Evidence of antigenic drift with viruses becoming more resistant over time suggests that these prevention modalities will need to be updated over time and that combinations of antibodies will be necessary to achieve coverage in passive immunization studies. We further show that it may be more difficult to obtain protection in the genetically diverse clade C epidemic compared to RV144 where the epidemic is less diverse, although it should be noted that the correlates of infection risk are yet to be defined in the clade C setting.
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    Modulation of female genital tract-derived dendritic cell migration and activation in response to inflammatory cytokines and toll-like receptor agonists
    (Public Library of Science, 2016) Shey, Muki S; Maharaj, Niren; Archary, Derseree; Ngcapu, Sinaye; Garrett, Nigel; Karim, Salim Abdool; Passmore, Jo-Ann S
    HIV transmission across the genital mucosa is a major mode of new HIV infections in women. The probability of infection may be influenced by several factors including recruitment and activation of HIV target cells, such as dendritic cells (DCs) and cytokine production, associated with genital inflammation. We evaluated the role of inflammatory cytokines and TLR signaling in migration and activation of genital tract DCs in the human cervical explant model. Hysterectomy tissues from 10 HIV-negative and 7 HIV-positive donor women were separated into ecto- and endocervical explants, and incubated with inflammatory cytokines (TNF-α, IL-1β, IL-8, MIP-1β) or agonists for TLR4 (LPS), TLR2/1 (PAM3) and TLR7/8 (R848). Migration (frequency) and activation (HLA-DR expression) of myeloid and plasmacytoid DCs and Langerhans cells were measured by flow cytometry. We observed that cytokines, LPS and PAM3 induced activation of migrating myeloid and plasmacytoid DCs. LPS induced a 3.6 fold lower levels of migration of plasmacytoid DCs from HIV-infected women compared with HIV-uninfected women (median activation indices of 2.932 vs 0.833). There was however a 4.5 fold increase in migration of Langerhans cells in HIV-infected compared with HIV-uninfected women in response to cytokines (median activation indices of 3.539 vs 0.77). Only TLR agonists induced migration and activation of DCs from endocervical explants. Hormonal contraception use was associated with an increase in activation of DC subsets in the endo and ectocervical explants. We conclude that inflammatory signals in the female genital tract induced DC migration and activation, with possible important implications for HIV susceptibility of cervical tissues.
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    No evidence for selection of HIV-1 with enhanced Gag-Protease or Nef function among breakthrough infections in the CAPRISA 004 tenofovir microbicide trial
    (Public Library of Science, 2013) Chopera, Denis R; Mann, Jaclyn K; Mwimanzi, Philip; Omarjee, Saleha; Kuang, Xiaomei T; Ndabambi, Nonkululeko; Goodier, Sarah; Martin, Eric; Naranbhai, Vivek; Karim, Salim Abdool
    BACKGROUND: Use of antiretroviral-based microbicides for HIV-1 prophylaxis could introduce a transmission barrier that inadvertently facilitates the selection of fitter viral variants among incident infections. To investigate this, we assessed the in vitro function of gag-protease and nef sequences from participants who acquired HIV-1 during the CAPRISA 004 1% tenofovir microbicide gel trial. Methods and RESULTS: We isolated the earliest available gag-protease and nef gene sequences from 83 individuals and examined their in vitro function using recombinant viral replication capacity assays and surface protein downregulation assays, respectively. No major phylogenetic clustering and no significant differences in gag-protease or nef function were observed in participants who received tenofovir gel versus placebo gel prophylaxis. CONCLUSION: Results indicate that the partial protective effects of 1% tenofovir gel use in the CAPRISA 004 trial were not offset by selection of transmitted/early HIV-1 variants with enhanced Gag-Protease or Nef fitness.
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    Optimal combinations of broadly neutralizing antibodies for prevention and treatment of HIV-1 Clade C infection
    (Public Library of Science, 2016) Wagh, Kshitij; Bhattacharya, Tanmoy; Williamson, Carolyn; Robles, Alex; Bayne, Madeleine; Garrity, Jetta; Rist, Michael; Rademeyer, Cecilia; Yoon, Hyejin; Lapedes, Alan; Gao, Hongmei; Greene, Kelli; Louder, Mark K; Kong, Rui; Karim, Salim Abdool; Burton, Dennis R; Barouch, Dan H; Nussenzweig, Michel C; Mascola, John R; Morris, Lynn; Montefiori, David C; Korber, Bette; Seaman, Michael S
    Author Summary In recent years, a new generation of monoclonal antibodies has been isolated from HIV-1 infected individuals that exhibit broad and potent neutralizing activity when tested against diverse strains of virus. There is a high level of interest in the field in determining if these antibodies can be used to prevent or treat HIV-1 infection. Because HIV-1 is adept at escaping from immune recognition, it is generally thought that combinations of multiple antibodies targeting different sites will be required for efficacy, much the same as seen for conventional antiretroviral drugs. How many and which antibodies to include in such combinations is not known. In this study, a new mathematical model was developed and used to accurately predict various measures of neutralizing activity for all possible combinations having a total of 2, 3, or 4 of the most promising antibodies. Through a systematic and comprehensive comparison, we identified optimal combinations of antibodies that best complement one another for enhanced anti-viral activity, and therefore may be most effective for the prevention or treatment of HIV-1 infection. These results provide important parameters that inform the selection of antibodies to develop for clinical use.
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    Transmission of HIV-1 CTL escape variants provides HLA-mismatched recipients with a survival advantage
    (Public Library of Science, 2008) Chopera, Denis R; Woodman, Zenda; Mlisana, Koleka; Mlotshwa, Mandla; Martin, Darren P; Seoighe, Cathal; Treurnicht, Florette; Rosa, Debra Assis de; Hide, Winston; Karim, Salim Abdool
    Author Summary Following infection with HIV, it is well established that a person's genetic makeup is a major determinant of how quickly they will progress to AIDS. Particularly important is the class I Human leukocyte antigen (HLA) gene that is responsible for alerting the immune system to HIV's presence. One of the reasons our immune systems are unable to beat HIV is that the virus can mutate to forms that our HLA genes no longer recognise. However, some people have versions of the HLA gene (for example HLA-B*57 and HLA-B*5801) that are known to force HIV to tolerate mutations that damage its ability to reproduce. Slower HIV reproduction is thought to be one reason that HLA-B*57 and HLA-B*5801 positive people progress to AIDS more slowly than most other HIV infected persons. We report here on a study of HLA-B*57 and HLA-B*5801 negative women in which better control of disease tended to be associated with their being infected with viruses carrying mutations that have been previously shown to reduce replication. These mutations characterise viruses found infecting HLA-B*57 and HLA-B*5801 positive people. This indicates for the first time that HLA-B*57 or HLA-B*5801 negative people that are infected by such reproductively compromised viruses may also experience better survival prospects.