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.
- Department of Experimental Medical Science
- Medstrand, Patrik, Supervisor
- Fenyö, Eva Maria, Supervisor
- Kvist, Anders, Supervisor
|Award date||2010 Dec 17|
|Publication status||Published - 2010|
Place: Belfragesalen, BMC D15, Sölvegatan 19, Lund
Name: Vandamme, Anne-Mieke
Affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium
The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Molecular Virology (013212007)
- Pharmacology and Toxicology
- disease progression
- coreceptor tropism
- soluble immune markers