Viral Correlates of HIV-1 Disease

Abstract

The transmission of HIV and the progression of HIV disease are influenced not only by a large number of human host factors, but also by certain correlates of the ever fluctuating virus quasispecies. The present review article aims at providing the current state of knowledge as well as an in-depth critical discussion of recent developments on the potential effects of HIV subtype, phenotype and attenuation on HIV disease. Despite the extensive research, several questions regarding the precise role that each of these correlates plays in human AIDS pathogenesis remain unanswered. Unraveling these roles is expected to aid the continued quest for truly effective antiretroviral drug regimens and preventive vaccines.

Chemokine Receptors as Therapeutic Targets in HIV Infection

“…Before the identification of the coreceptors, three biological properties were the criteria used to classify the phenotype of HIV variants: (i) the preference for specific target cells (cellular tropism) that distinguished between macrophage (M)-tropic and laboratory T-cell line (T)-tropic viruses; (ii) cytopathology, which distinguished between syncytium-inducing (SI) and non-syncytium-inducing (NSI) strains based on the capacity or not to form syncytia (i.e., giant multinucleated cells) through cell fusion in the MT-2 cell line; and (iii) replicative capacity, which mainly considered the in vitro growth kinetics of viral strains in culture and distinguished between slow/low (S/L) and rapid/high viruses (R/H) (reviewed in [43]). …”

“…Swapping the V3 region alone often suffices to switch the coreceptor tropism of a viral clone from R5 to X4 and vice versa [45]. Furthermore, the charge of the V3 region appears to be an important parameter affecting biological phenotype and, tropism, although it alone cannot be used as a marker for phenotype prediction; in general, however, higher net charges ( +5) characterize X4 variants compared to the lower V3 region net charges ( +4) of R5 variants typically associated with acute infection (reviewed in [43]). The increase of the overall positive charge of the V3 region that may switch the viral phenotype results from the introduction of basic amino acid residues at one of the two positions 11 and/or 25 of the V3 [46,47], a property that may not be shared by the uncommon subtype C CXCR4-using strains (reviewed in [48]).…”

“…Regardless of the route of HIV transmission, R5 viruses seem to prevail in the vast majority of primary and early stage HIV infection cases, whilst the X4 phenotype evolves in vivo in approximately 40-50% of (subtype B or D) infected subjects, usually 5-7 years after infection (reviewed in [43,53]). Recent transmitted/founder virus genetic studies confirmed that only R5 (and typically a single R5 virus isolate) and in a few instances R5X4, but not X4 HIV-1, are initially transmitted [54,55].…”

“…The emergence of X4 viruses in a proportion of cases correlates with accelerated disease progression [43,53]. The virological or immunological basis of the selection mechanism is still debated; in other words, it is still unclear whether disease progression is accelerated as a direct consequence of the emergence or predominance of X4 isolates, or, conversely, whether the declining competence of the host immune system permits the outgrowth of viral strains with increased replicative capacity [43].…”

“…The virological or immunological basis of the selection mechanism is still debated; in other words, it is still unclear whether disease progression is accelerated as a direct consequence of the emergence or predominance of X4 isolates, or, conversely, whether the declining competence of the host immune system permits the outgrowth of viral strains with increased replicative capacity [43]. The pathogenicity of X4 viruses seems to be greater than that displayed by R5 strains both in vitro and probably in vivo, as suggested by experiments in macaques [22].…”