Progression to AIDS in South Africa is associated with both reverting and compensatory viral mutations

We lack the understanding of why HIV-infected individuals in South Africaprogress to AIDS. We hypothesised that in end-stage disease there is a shiftingdynamic between T cell imposed immunity and viral immune escape, which, throughboth compensatory and reverting viral mutations, results in increased viralfitness, elevated plasma viral loads and disease progression. We explored how Tcell responses, viral adaptation and viral fitness inter-relate in South Africancohorts recruited from Bloemfontein, the Free State(n = 278) and Durban, KwaZulu-Natal(n = 775). Immune responses were measured byγ-interferon ELISPOT assays. HLA-associated viral polymorphisms weredetermined using phylogenetically corrected techniques, and viral replicationcapacity (VRC) was measured by comparing the growth rate of gag-proteaserecombinant viruses against recombinant NL4-3 viruses. We report that inadvanced disease (CD4 counts <100 cells/µl), T cell responses narrow,with a relative decline in Gag-directed responses (p<0.0001). This isassociated with preserved selection pressure at specific viral amino acids(e.g., the T242N polymorphism within the HLA-B*57/5801 restricted TW10epitope), but with reversion at other sites (e.g., the T186S polymorphism withinthe HLA-B*8101 restricted TL9 epitope), most notably in Gag and suggestiveof “immune relaxation”. The median VRC from patients with CD4 counts<100 cells/µl was higher than from patients with CD4 counts ≥500cells/µl (91.15% versus 85.19%,p = 0.0004), potentially explaining the rise in viral loadassociated with disease progression. Mutations at HIV Gag T186S and T242Nreduced VRC, however, in advanced disease only the T242N mutants demonstratedincreasing VRC, and were associated with compensatory mutations(p = 0.013). These data provide novel insights into themechanisms of HIV disease progression in South Africa. Restoration of fitnesscorrelates with loss of viral control in late disease, with evidence for bothpreserved and relaxed selection pressure across the HIV genome. Interventionsthat maintain viral fitness costs could potentially slow progression.