HIV-1 in genital tract and plasma of women: Compartmentalization of viral sequences, coreceptor usage, and glycosylation

Abstract

Worldwide, 90% of HIV-1 infections are transmitted heterosexually. Because the genital mucosa are the sites of initial contact with HIV-1 for most exposed individuals, study of the virus from the genital tract is critical for the development of vaccines and therapeutics. Previous analyses of HIV-1 in various tissues have documented compartmentalization of viral genomes. Whether compartmentalization was associated with viral phenotypic differences or immune status, however, was not well understood. We compared HIV-1 gp120 env sequences from the genital tract and plasma of 12 women. Eight women displayed compartmentalized HIV-1 RNA genomes, with viral sequences from each site that were clearly discrete, yet phylogenetically related. The remaining four exhibited env sequences that were intermingled between the two sites. Women with compartmentalized HIV-1 genomes had higher CD4 ؉ cell counts than those displaying intermingled strains (P ‫؍‬ 0.02). Intrapatient HIV-1 recombinants comprising sequences that were characteristic of both sites were identified. We next compared viral phenotypes in each compartment. HIV-1 coreceptor usage was often compartmentalized (P < 0.01). The number of N-linked glycosylation sites, associated with neutralization resistance, also differed between compartments (P < 0.01). Furthermore, disparities between the density of gp120 glycosylations in each compartment correlated with higher CD4 ؉ counts (P ‫؍‬ 0.03). These data demonstrate that the genital tract and plasma can harbor populations of replicating HIV-1 with different phenotypes. The association of higher CD4 ؉ cell counts with compartmentalization of viral genomes and density of gp120 glycosylations suggests that the immune response influences the development of viral genotypes in each compartment. These findings are relevant to the prevention and control of HIV-1 infection.

Human Immunodeficiency Virus Type 1 Genomic RNA Sequences in the Female Genital Tract and Blood: Compartmentalization and Intrapatient Recombination

“…These data provide strong evidence for the presence of distinct populations of HIV-1 replicating in each site. Although we did not discern sequences that conferred different phenotypes on the viruses in each compartment, such differences have been observed (8,9,24,44,54). The detailed documentation of HIV-1 compartmentalization presented here underscores the potential for distinct, clinically relevant characteristics such as antiretroviral resistance or coreceptor usage in separate, biologically significant compartments.…”

“…pressure in the separate compartments (61). Another study, which examined women with a spectrum of immune states, demonstrated an association of higher CD4 ϩ cell counts and compartmentalization of HIV-1 env sequences, providing evidence that the immune response influences the development of viral genotypes in each compartment (24).…”

“…Although much HIV-1 variation can be attributed to the error-prone nature of reverse transcriptase, viral recombination provides the opportunity for evolutionary leaps, with genetic consequences far greater than those resulting from the steady accumulation of individual mutations (35). Recent work suggests that intrapatient HIV-1 recombination may occur very frequently (13,23,24,32), but recombination between quasispecies from different anatomic sites within the same individual has not been studied extensively.…”

“…Compartmentalization has been rigorously documented in various different tissues, including the brain, blood and tissue lymphocytes, and plasma (5,27,41,59,61). HIV-1 sequence heterogeneity has also been observed in several pioneering studies of blood and genital secretions of infected women (18,24,39,45,51), but complete RNA genomes from the genital tract have not been fully characterized on a molecular level. Study of HIV-1 in the female genital tract has been hampered by the difficulty of cultivating virus from this biologically critical site (28).…”

HIV-1 Pathogenesis: The Virus

“…There is no obvious single tissue mass (equivalent to the prostate, for example) that could provide a source of localized virus production. Several studies have reported compartmentalization of viral sequences in the FMTwithin at least a subset of subjects (Poss et al 1998;Kemal et al 2003;Adal et al 2005;Andreoletti et al 2007). More recently, this compartmentalization was interpreted to be largely the result of clonal amplification (Bull et al 2009).…”