RESUMO
HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although risk of progression may vary among patients carrying this allele. The interplay between HIV-1 evolutionary rate variation and risk of progression to AIDS in HLA-B*5701 subjects was studied using longitudinal viral sequences from high-risk progressors (HRPs) and low-risk progressors (LRPs). Posterior distributions of HIV-1 genealogies assuming a Bayesian relaxed molecular clock were used to estimate the absolute rates of nonsynonymous and synonymous substitutions for different set of branches. Rates of viral evolution, as well as in vitro viral replication capacity assessed using a novel phenotypic assay, were correlated with various clinical parameters. HIV-1 synonymous substitution rates were significantly lower in LRPs than HRPs, especially for sets of internal branches. The viral population infecting LRPs was also characterized by a slower increase in synonymous divergence over time. This pattern did not correlate to differences in viral fitness, as measured by in vitro replication capacity, nor could be explained by differences among subjects in T cell activation or selection pressure. Interestingly, a significant inverse correlation was found between baseline CD4+ T cell counts and mean HIV-1 synonymous rate (which is proportional to the viral replication rate) along branches representing viral lineages successfully propagating through time up to the last sampled time point. The observed lower replication rate in HLA-B*5701 subjects with higher baseline CD4+ T cell counts provides a potential model to explain differences in risk of disease progression among individuals carrying this allele.
Assuntos
Linfócitos T CD4-Positivos , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/genética , Antígenos HLA-B , Teorema de Bayes , Biologia Computacional , Progressão da Doença , Proteína do Núcleo p24 do HIV/classificação , Proteína do Núcleo p24 do HIV/genética , Infecções por HIV/epidemiologia , Humanos , Dados de Sequência Molecular , Mutação/genética , Replicação Viral/genéticaRESUMO
Human immunodeficiency virus type 1 (HIV-1) has been classified into three main groups and 11 distinct subtypes. Moreover, several circulating recombinant forms (CRFs) of HIV-1 have been recently documented to have spread widely causing extensive HIV-1 epidemics. A subtype, initially designated I (CRF04_cpx), was documented in Cyprus and Greece and was found to comprise regions of sequence derived from subtypes A and G as well as regions of unclassified sequence. Re-analysis of the three full-length CRF04_cpx sequences that were available revealed a mosaic genomic organization of unique complexity comprising regions of sequence from at least five distinct subtypes, A, G, H, K and unclassified regions. These strains account for approximately 2% of the total HIV-1-infected population in Greece, thus providing evidence of the great capability of HIV-1 to recombine and produce highly divergent strains which can be spread successfully through different infection routes.
Assuntos
Proteínas do Capsídeo , HIV-1/genética , Proteínas Virais , Capsídeo/classificação , Capsídeo/genética , Chipre , Produtos do Gene gag/classificação , Produtos do Gene gag/genética , Produtos do Gene pol/classificação , Produtos do Gene pol/genética , Produtos do Gene vif/classificação , Produtos do Gene vif/genética , Grécia , Antígenos HIV/classificação , Antígenos HIV/genética , Proteína do Núcleo p24 do HIV/classificação , Proteína do Núcleo p24 do HIV/genética , Proteína gp120 do Envelope de HIV/classificação , Proteína gp120 do Envelope de HIV/genética , Proteína gp41 do Envelope de HIV/classificação , Proteína gp41 do Envelope de HIV/genética , HIV-1/classificação , HIV-1/isolamento & purificação , Humanos , Filogenia , Recombinação Genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana , Produtos do Gene vif do Vírus da Imunodeficiência HumanaRESUMO
The genetic subtype was identified in gag and env of 219 HIV-1-positive samples collected in different African countries, 44 from Senegal, 55 from Cameroon, 82 from Gabon, and 38 from Djibouti. In total, 20 (9.1%) samples had discordant subtypes between gag and env, 6 of 44 (13.9%) in Senegal, 4 of 55 (7.2%) in Cameroon, 1 of 38 (2.6%) in Djibouti, and 10 of 82 (12.1%) in Gabon. Subtypes A and G were predominantly involved in the recombination events. Phylogenetic tree analysis of gag showed that an important number of the A sequences form a distinct subcluster with the AG-IBNG prototype strain (a complex A/G mosaic virus): 27 of 32 (84.3%) in Senegal, 12 of 17 (70.6%) in Nigeria, 24 of 39 (61.5%) in Cameroon, and 38 of 70 (54.3%) in Gabon. Full-length genome analysis of 3 and additional sequences in pol for 10 such strains confirmed that they have a similar complex A/G mosaic genomic structure. These data suggest that in West Africa, most probably between 60% and 84% of the subtype A viruses are recombinant AG-IBNG viruses. This finding has potential implications on future vaccine, diagnostic, and treatment strategies. The actual and future role of these viruses in the global pandemic must be monitored in all new molecular epidemiologic studies, a discrimination between subtype A and AG-IBNG-like viruses is necessary.
