Human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) are both causative agents of AIDS, with similar pathogenic characteristics. However, the rate of disease progression is highly variable both within and between HIV-1 and HIV 2, but the mechanisms involved in modulating the rate of disease progression remain poorly understood. Host genetics account for some of the variation within each virus type but viral genetic factors were recently described to be more important than previously anticipated. The aim of this thesis work was to investigate the association between some viral genetic factors and disease progression. More specifically, we investigated the impact of HIV-1 subtype and HIV-2 evolution on disease progression.
The HIV-1 subtype was determined based on sequencing of the C2-V3 region of env. The rate of disease progression was compared among 139 individuals from Guinea-Bissau infected with the three major subtypes/CRFs; A3, CRF02_AG and A3/02. Infection with A3/02, a recombinant form with a break-point in the C2 region, was associated with a faster disease progression compared with infection with sub-subtype A3. Infection with CRF02_AG resulted in an intermediate disease progression. Our results suggested that recombinant forms may be more aggressive than their parental variants. Near full-length sequencing of six A3/02 samples, showed that the previously identified recombination break-point in the C2 region, was the only break-point shared by all six samples, identifying this region as a possible modulator of disease progression.
We also investigated the evolution of the HIV-2 V1-C3 region of env in 16 individuals stratified as fast or slow progressors based on CD4+ T cell dynamics. We found that disease progression as defined by CD4+ T cell level, rather than CD4+ T cell decline rate, was associated with evolutionary parameters. Most strikingly, a fast disease progression, as defined by CD4+ T cell level, was associated with an almost twice as high evolutionary rate compared with a slow disease progression. This difference was accounted for by higher rates of both nonsynonymous and synonymous substitutions, indicating that viral generation time and/or replication rates are the main modulators of the HIV-2 evolutionary rate. Fast and slow disease progression was also distinguished by different evolutionary patterns of Env glycosylation. The evolution of the other investigated Env molecular properties did not differ between progressor groups and was suggested to be more limited than what has previously been described for HIV-1.
This thesis work increases our understanding of the HIV pathogenesis by adding insight into previously unknown characteristics of HIV-1 and HIV-2 pathogenesis. Further work, building on these data, may reveal important predictors of disease progression and identify new targets for drug development.
- Institutionen för experimentell medicinsk vetenskap
- Medstrand, Patrik, handledare
- Jansson, Marianne, handledare
- Esbjörnsson, Joakim, handledare
- Norrgren, Hans, handledare
|Tilldelningsdatum||2015 jan. 30|
|Status||Published - 2015|
Place: Belfragesalen, BMC D15, Klinikgatan 32, Lund
Name: Taveria, Nuno
Affiliation: Research Institute for Medicines, Universidade de Lisboa, Lisbon, Portugal
- Medicinska grundvetenskaper