HIV pathogenesis and Vaccine research

is headed by Koleka Mlisana.

 The goals of HIV vaccines are to prevent infection and/or to slow the progression of HIV infection to clinical AIDS. Two of the key challenges in vaccine development are lack of clarity on what immune responses are needed and which components of the virus need to be targeted to protect against HIV infection. In an attempt to address these challenges, CAPRISA has been focusing since inception, on the earliest transmitted viruses and the earliest immune responses in acute HIV infection.

The pivotal study in this research programme is the CAPRISA 002 Acute Infection study which aims to characterize viral set point and clinical progression in subtype C infection and identify host, immunology and viral factors that predict disease progression.

The CAPRISA 002 Acute Infection study has shown that 1) there is a rapid loss of about half of the pre-infection CD4+ T cells during acute subtype C HIV-1 infection, 2) High proportion (~25%) of participants have rapid disease progression, needing antiretroviral therapy in the first 12 months of infection, 3) the severity of clinical signs and symptoms during acute HIV-1 infection are correlated with enrolment viral load but not with subsequent disease progression, 4) Diversity of virus at transmission impacts on disease progression, 5) Magnitude and breadth of HIV-1 specific CD8+ T cell gamma interferon Elispot responses at 3 months post-infection does not correlate with set point viral load, 6) Individuals with low set point viral loads have more early differentiated CD8+ T cells, 7) women with acute HIV infection had significantly elevated levels of inflammatory cytokines in their genital tract and plasma specimens, compared with HIV-negative control women, 8) Transmission of CTL escape variants provides HLA mismatched individuals with a survival advantage, 9) HLA-B*5801 is not associated with lower viral loads in the first year of infection, 10) The C3-V4 region is a major target of autologous neutralizing antibodies in HIV-1 subtype C infection, 11) Analysis of neutralization escape suggests limited neutralizing antibody specificities in early HIV-1 subtype C infection, 12) Early neutralization breadth in an HIV-1 subtype C infected individual is conferred by antibodies targeting the V1/V2 region, 13) Broad HIV-1 neutralization is mediated by plasma antibodies against the gp41 membrane proximal external region, 14) Approximately 80% of acute HIV infections involve a single virus (genetic bottleneck) in subtype C acute infection, 15) Reduced expression of TRIM5α is associated with higher likelihood of HIV-1 infection, 16) APOBEC3G mRNA levels were lower in peripheral blood mononuclear cells from HIV-1 –infected compared to HIV-1 uninfected subjects, 17) Chemokine copy number variations (CNV) on chromosome 17q12 can be an important determinant of HIV susceptibility.

 CAPRISA is also involved in other collaborative studies in acute HIV infection; including a collaboration with the Center for HIV AIDS Vaccine Immunology (CHAVI) on the CHAVI 001 Acute Infection study and a collaboration with the University of Washington on potential mechanism of resistance to infection in highly exposed seronegative (HEPS) women

 CAPRISA participates in the NIH-funded HIV Vaccine Trial Network (HVTN) and is one of the sites conducting the HVTN 503 trial, a multicenter double-blind randomized placebo-controlled Phase IIB test-of-concept trial to evaluate the safety and efficacy of a 3-dose regimen of the Clade B-based Merck Adenovirus serotype 5 HIV-1 gag/pol/nef vaccine in HIV-1-uninfected adults in South Africa. This is one of the 2 Merck vaccine trials that have recently been prematurely terminated; CAPRISA is currently continuing with participant follow-up but enrolments and vaccinations have been discontinued.  In preparation of future vaccine trials in adolescents, CAPRISA is one of the sites participating in the South African Studies on HIV in Adolescents (SASHA), led by University of Cape Town researchers.

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