Frequent CXCR4 tropism of HIV-1 subtype A and CRF02_AG during late-stage disease - indication of an evolving epidemic in West Africa

Abstract

BackgroundHIV-1 is one of the fastest evolving pathogens, and is distinguished by geographic and genetic variants that have been classified into different subtypes and circulating recombinant forms (CRFs). Early in infection the primary coreceptor is CCR5, but during disease course CXCR4-using HIV-1 populations may emerge. This has been correlated with accelerated disease progression in HIV-1 subtype B. Basic knowledge of HIV-1 coreceptor tropism is important due to the recent introduction of coreceptor antagonists in antiretroviral therapy, and subtype-specific differences regarding how frequently HIV-1 CXCR4-using populations appear in late-stage disease need to be further investigated. To study how frequently CXCR4-using populations appear in late-stage disease among HIV-1 subtype A and CRF02_AG, we evaluated the accuracy of a recombinant virus phenotypic assay for these subtypes, and used it to determine the HIV-1 coreceptor tropism of plasma samples collected during late-stage disease in Guinea-Bissau. We also performed a genotypic analysis and investigated subtype-specific differences in the appearance of CXCR4 tropism late in disease.ResultsWe found that the recombinant virus phenotypic assay accurately predicted HIV-1 coreceptor tropism of subtype A and CRF02_AG. Over the study period (1997-2007), we found an increasing and generally high frequency of CXCR4 tropism (86%) in CRF02_AG. By sequence analysis of the V3 region of our samples we developed a novel genotypic rule for predicting CXCR4 tropism in CRF02_AG, based on the combined criteria of the total number of charged amino acids and net charge. This rule had higher sensitivity than previously described genotypic rules and may be useful for development of future genotypic tools for this CRF. Finally, we conducted a literature analysis, combining data of 498 individuals in late-stage disease, and found high amounts of CXCR4 tropism for all major HIV-1 subtypes (60-77%), except for subtype C (15%).ConclusionsThe increase in CXCR4 tropism over time suggests an evolving epidemic of CRF02_AG. The results of the literature analysis demonstrate the need for further studies investigating subtype-specific emergence for CXCR4-tropism; this may be particularly important due to the introduction of CCR5-antagonists in HIV treatment regimens.

A Conserved Determinant in the V1 Loop of HIV-1 Modulates the V3 Loop To Prime Low CD4 Use and Macrophage Infection

“…Of note, clade D viruses have been associated with faster disease progression (1,14,19,20,45) and a higher frequency of dementia (40). In addition, CXCR4 tropism was common among CRF02_AG viruses, a sign of a mature HIV epidemic (15). It is thus possible that an increased frequency of G153 may simply reflect a high prevalence of R5 viruses with increased macrophage tropism late in disease (18,25,44).…”

Potent Intratype Neutralizing Activity Distinguishes Human Immunodeficiency Virus Type 2 (HIV-2) from HIV-1

“…For the first time, this study also allowed analysis of NAc in plasma of dually HIV-1/HIV-2 (HIV-D)-infected individuals. NAc in plasma was tested against a panel of HIV-1 and HIV-2 primary isolates, including isolates of the CRF02_AG subtype, which is currently the most common HIV-1 subtype in this area (5,17). The results show that the potency of intratype neutralization differed between HIV-1 and HIV-2 infection, where high-titer NAc characterized the plasma of HIV-2-infected individuals.…”

Dilemma of concepts and strategies for the prevention of spread of HIV in relation to human behavior, law and human rights

“…Human beings are the exclusive hosts, therefore human sexual behavior indirectly boosts these characteristic traits of HIV and offers optimal conditions for its spread and ongoing evolution (Kandathil et al, 2005;Taylor et al, 2009;Esbjörnsson et al, 2010;Zhang et al, 2010), besides special situations with injecting drug users (IDUs), e.g., sharing vehicles like needles or syringes contaminated with HIV.…”