PhD

Abstract: The two genetically related human lentiviruses known today, HIV-1 (which is pandemic) and HIV-2 (which mainly is confined to West Africa), are the causative agents of AIDS. Progressive immune dysfunction and AIDS develop in most cases of untreated HIV-1 infection, but only in approximately 25-30% of HIV-2 infected individuals. The V1-V3 region of the HIV-1 env gp120 is important for HIV-1 coreceptor use, and represents an informative region for both molecular epidemiology and intrapatient phylogenetic analyses due to high level of genetic variation. In this doctoral dissertation, HIV-1 V1-V3 sequences in combination with clinical disease markers were used to investigate HIV-1 evolution, disease progression, coreceptor tropism and molecular epidemiology of HIV-1. All sequences were derived from single (HIV-1 only) or dual-infected (HIV-1 and HIV-2) individuals from Guinea-Bissau, West Africa. The main findings was that CRF02_AG represents the most common form of HIV-1 in Guinea-Bissau, and that HIV-1 was introduced into the country on at least six different occasions between 1976 and 1981. Dual-infected individuals had a 46% lower mortality rate and a 53% longer progression-time to AIDS compared to single-infected individuals. CD4+ T cell counts were higher at corresponding time-points after infection among dual-infected individuals, reflecting the slower disease progression rate at the cellular immune level. In addition, CD8+ T cell counts were increasing at a faster rate in single than in dual-infected individuals. Stratified analyses showed that these observations were most prominent among the subgroup of dual-infected individuals that became HIV-1 infected after an established HIV-2 infection. Moreover, the HIV-1 genetic diversity was significantly lower in dual than in single-infected individuals at comparable time-points after infection. HIV-1 coreceptor tropism was investigated in late-stage disease by the use of a recombinant virus phenotypic assay that were confirmed to accurately predict the coreceptor tropism of HIV-1 subtype A and CRF02_AG. CXCR4 tropism has been coupled to an increased HIV-1 disease progression rate in late-stage disease. We found that HIV-1 CRF02_AG CXCR4 tropism was frequent (86%) and increased over time on the population level, indicating an evolving epidemic. In addition, a literature analysis showed a similar evolving epidemic for HIV-1 subtype C. Genotypic analysis suggested that the total number of charged amino acids could be important in predicting HIV-1 CRF02_AG coreceptor tropism. Finally, HIV-1 CXCR4-tropism was more common in single (79%) than in dual-infected individuals (35%). Understanding the underlying mechanisms responsible for the inhibitory effects exerted by HIV-2 against HIV-1 could be important for the development of future HIV-1 vaccines and therapeutics.