The Class I Human Leukocyte Antigen (HLA) locus determines the HIV peptides targeted by cytotoxic T-lymphocytes (CTLs) and is an important genetic factor that affects the rate of disease progression in HIV-1 infected individuals (4;5). A major contributor to ongoing HIV-1 diversification is continual escape from anti- HIV host CTL responses (21;22). CTL escape has been associated with increased viral loads and more rapid disease progression (11-14;29). However CTL escape variants may also have lower replicative fitness than the wild-type and are associated with slower disease progression (16;17;41;48). In addition, viruses harbouring CTL escape mutations undergo reversion to wild-type following transmission to HLA-mismatched individuals providing further evidence that CTL escape has an impact of viral fitness (6;7;9;10) . Acute HIV infection is associated with massive destruction of the mucosal immune system (1;2) and higher viral loads in acute infection have been associated with a higher viral load at set-point (3). Factors that influence the severity of acute infection may therefore have long term impact on subsequent disease progression. From a virological perspective, two such factors include (a) inherent properties of the virus including infection with viruses containing attenuating CTL mutations which are a consequence of viral adaptation in a previous host and (b) the emergence of new CTL escape mutations following infection. The counterbalance of these two evolutionary pathways may have implications in control of viral replication in acute infection. We hypothesize that an interacting network of attenuating mutations may be responsible for lower viral loads observed in some people. Through a detailed investigation of viral sequences generated from HIV-1 subtype C infected, drug naive individuals we aim to: first, identify mutations associated with CTL escape that emerge during the first 6 months following HIV-1 subtype C infection;second, to quantify the frequency of CTL escape mutations in transmitted viruses and the timing of their reversion over two years following their transmission to HLA mismatched hosts;and third, to determine the impact on disease progression of CTL escape mutations detected in viruses from individuals during acute infection. The overall objective of this project is to identify attenuating mutations that impact of clinical disease progression as measured by CD+4 T-cell count and viral loads. Current opinion is that first generation CTL based vaccines are likely to be only partially effective. We propose that such vaccines should contain epitopes where escape is associated with a fitness cost to the virus as this might drive the attenuation of viruses in individuals who become infected despite vaccination. PUBLIC HEALTH RELEVANCE: It is estimated that there are over 5 million South Africans infected with the HIV virus, representing roughly 12% of the population. Vaccine development is a major focus of research in this country. This project aims to identify attenuating CTL mutation in HIV. First generation CTL based vaccines are likely to be only partially effective. We propose that such vaccines should contain epitopes where escape is associated with a fitness cost to the virus as this might drive the attenuation of viruses in individuals who become infected despite vaccination. This project was previously funded through CIPRA (U19 A151794-01). .