Browsing by Author "Hide, Winston."

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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.
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.
Transmission of HIV-1 CTL escape variants provides HLA - mismatched recipients with a survival advantage.
(Plos., 2007) Chopera, Denis Rutendo.; Woodman, Zenda.; Mlisana, Koleka Patience.; Mlotshwa, Mandla.; Martin, Darren Patrick.; Seoighe, Cathal.; Treurnicht, Florette K.; de Assis Rosa, Debra.; Hide, Winston.; Abdool Karim, Salim Safurdeen.; Gray, Clive M.; Williamson, Carolyn.
One of the most important genetic factors known to affect the rate of disease progression in HIV-infected individuals is the genotype at the Class I Human Leukocyte Antigen (HLA) locus, which determines the HIV peptides targeted by cytotoxic T-lymphocytes (CTLs). Individuals with HLA-B*57 or B*5801 alleles, for example, target functionally important parts of the Gag protein. Mutants that escape these CTL responses may have lower fitness than the wild-type and can be associated with slower disease progression. Transmission of the escape variant to individuals without these HLA alleles is associated with rapid reversion to wild-type. However, the question of whether infection with an escape mutant offers an advantage to newly infected hosts has not been addressed. Here we investigate the relationship between the genotypes of transmitted viruses and prognostic markers of disease progression and show that infection with HLA-B*57/B*5801 escape mutants is associated with lower viral load and higher CD4+ counts.