A Group of V3 Sequences from Human Immunodeficiency Virus Type 1 Subtype E Non-Syncytium-Inducing, CCR5-Using Variants Are Resistant to Positive Selection Pressure

Abstract

In a human immunodeficiency virus type 1 (HIV-1)-infected individual, immune-pressure-mediated positive selection operates to maintain the antigenic polymorphism on the gp120 third variable (V3) loop. Recently, we suggested on the basis of sequencing C2/V3 segments from an HIV-1 subtype E-infected family that a V3 sequence lineage group of the non-syncytium-inducing (NSI) variants (group 1) was relatively resistant to positive selection pressure (35). To better understand the relationship between the intensity of positive selection pressure and cell tropism of the virus, we determined the linkage between each V3 genotype and its function of directing coreceptor preference and MT2 cell tropism. The biological characterization of a panel of V3 recombinant viruses showed that all of the group 1 V3 sequences could confer an NSI/CCR5-using (NSI/R5) phenotype on HIV-1 LAI , whereas the group 2 V3 sequence, which was more positively charged than the group 1 sequence, dictated mainly a syncytium-inducing, CXCR4-using (SI/X4) phenotype. Phylogenetic analysis of C2/V3 sequences encoding group 1 or 2 V3 suggested that the variants carrying group 1 V3 are the ancestors of the intrafamilial infection and persisted in the family, while the variants carrying group 2 V3 evolved convergently from the group 1 V3 variants during disease progression in the individuals. Finally, a statistical test showed that the V3 sequence that could dictate an NSI/R5 phenotype had a synonymous substitution rate significantly higher than the nonsynonymous substitution rate. These data suggest that V3 sequences of the subtype E NSI/R5 variants are more resistant to positive selection pressure than those of the SI/X4 variants.During the course of infection of an animal with a pathogen, amino acid sequence polymorphism is often generated in the surface antigenic sites. The mechanism to maintain this polymorphism is explained by positive Darwinian selection, which is thought to be caused by the immune-pressure-mediated host-parasite struggle referred to as antigenic drift (38-40, 43, 51). In this regard, it is generally accepted that a high degree of sequence polymorphism in the third variable (V3) loop within env gp120 of Human immunodeficiency virus type 1 (HIV-1) is maintained by positive selection, since the element consists of a major epitope for neutralizing antibodies (31, 47). Indeed, nonsynonymous substitution per nonsynonymous site (Ka) exceeded synonymous substitution per synonymous site (Ks) in the V3 loop (43, 58), and this tendency was enhanced with the duration of the immunocompetent period of infected individuals (23).On the other hand, the V3 loop element consists of a critical determinant for the target cell type preference of the virus (6, 41, 48). The loop specifies the coreceptor usage of HIV-1 (4, 5), probably via interaction with the coreceptor molecules (1, 15, 52). Therefore, nonsynonymous mutation in the V3 loop can result in generation of either defective virus or virus which alters cell tropism. When such an alteration is ...

Selection in ContextSequence data from this article have been deposited with the EMBL/GenBank Data Libraries under accession nos. AF016760, AF016761, AF016762, AF016763, AF016764, AF016765, AF016766, AF016767, AF016768, AF016769, AF016770, AF016771, AF016772, AF016773, AF016774, AF016775, AF016776, AF016777, AF016778, AF016779, AF016780, AF016781, AF016782, AF016783, AF016784, AF016785, AF016786, AF016787, AF016788, AF016789, AF016790, AF016791, AF016792, AF016793, AF016794, AF016795, AF016796, AF016797, A

“…Indeed, the relative fitnesses in recipients and nonrecipsystem recognition site of HIV-1, selective pressure for "escape mutants" should affect this region (Leigh ients of antiviral drug therapy are not significantly different using an exact test, indicating that the SI form has Brown and Holmes 1994;Rowland-Jones et al 2001). In this regard, recent in general a growth advantage over the NSI form when the immune system is severely compromised but not studies (Callaway et al 1999;Shiino et al 2000) provide evidence for the hypothesis that the V3 loop of the when the immune system is healthy. Table 4 indicates that this effect is due to a large 10-fold increase in the NSI form is more hidden from neutralizing antibody than is the SI V3 loop; that is, the amino acid changes growth rate of the SI form as the immune system goes from a healthy to a compromised state in subjects not necessary for the SI form simultaneously make SI more apparent to the immune system than NSI.…”

“…The purpose of this article is to examine selection in the same 15 subjects as in the Markham et al (1998) (Goudsmit 1997) and the target of host cell-type preference (Shiino et al 2000). The third variable domain study but to investigate a broader range of potential selective contexts.…”

“…In contrast, there is tion when the immune system is healthy. As the immune system becomes compromised and then collapses, selecno significant change in the growth rates of the NSI form, either overall or as a function of antiviral drug tion from this source should diminish and then disappear, and there should also be less of a growth inhibition therapy status, and the fitness values suggest that, if anything, NSI does better when the immune system on SI forms relative to NSI (Callaway et al 1999;Shiino et al 2000). The hypothesis of greater immune is healthy than when it is compromised-exactly the opposite of the SI pattern.…”

“…The earliest samples used in this two mutations yet do not dominate until late in infection implies that there is some sort of selective force modulatstudy were taken in 1989 and the last in 1993. The subset of individuals selected for this study was followed from ing this phenotypic switch (Callaway et al 1999;Shiino et al 2000). Hence, the V3 loop is a candidate the point of HIV-1 seroconversion and reflects different trajectories of CD4 T-cell counts.…”

Reevaluation of Amino Acid Variability of the Human Immunodeficiency Virus Type 1 gp120 Envelope Glycoprotein and Prediction of New Discontinuous Epitopes

“…Over the entire region of gp120, the number of synonymous substitutions per site was larger than that of nonsynonymous substitutions (35,38), implying that negative selection is predominant in the whole protein. However, several studies reported an excess of nonsynonymous substitutions with statistical significance in major epitopes such as the V2 (51) and V3 (3,4,49,51,52,68) regions in gp120. These observations imply that positive selection may be dominantly operating on these two regions.…”