Intrahost evolution of HIV-1 phenotypes
Sammanfattning: HIV-1 evolves constantly within an infected individual, due to its mutation-prone viral enzyme, high viral turnover and pressure from the host immune system. Therefore, viruses isolated at different time points from the same individual are never exactly the same and, accordingly, rarely function the same way. However, if we can understand how HIV-1 phenotypically evolves in the newly infected host and during disease progression, we may develop better therapeutics and perhaps halt the spread of the virus. This thesis is based on studies in which we have investigated how HIV-1 phenotypically evolves within infected individuals. We studied viruses emerging in infected adults, during late stage disease, and in vertically infected children, from shortly after birth until immunodeficiency. Some patients maintained viruses that exclusively used CC chemokine receptor 5 (CCR5) as coreceptor, R5 HIV-1, throughout the infection. Others had viruses whose coreceptor use was altered to include CXC chemokine receptor 4 (CXCR4). We analyzed sequentially obtained viruses from both groups of patients and studied phenotypic features in relation to molecular alterations in the viral envelope glycoproteins (Env). We found that the virus evolution at late stage disease toward increased infectivity and replicative capacity was fairly similar within patients harboring R5 or CXCR4-using HIV-1. The R5 HIV-1 also showed a decrease in trans-infection ability, mediated by the C-type lectin DC-SIGN, at end-stage disease. In addition, end-stage R5 HIV-1 were more sensitivity to certain broadly neutralizing antibodies. Furthermore, phenotypic alterations correlated with the decline in CD4+ T cell count during development of immunodeficiency. The observed evolution in phenotypic features also correlated with molecular alterations of the viral envelope glycoprotein gp120, with an increase in net positive charge and a loss of potential N-linked glycosylation sites (PNGS) at the end-stage of the disease. In addition, the efficiency of HIV-1 DC-SIGN use correlated with the presence of a specific glycan site in gp120. Studies on R5 HIV-1 from vertically infected children and their mothers demonstrated that efficient use of DC-SIGN for trans-infection do not appear to be a benefit for newly transmitted virus variants. Instead, the efficiency of virus DC-SIGN use increased during disease progression, from early after birth until immunodeficiency. These studies reveal that the phenotypes of R5 and CXCR4-using HIV-1 may evolve in an adaptive manner during disease progression and transmission.
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