Charged amino acid patterns of coreceptor use in the major subtypes of human immunodeficiency virus type 1

Abstract

Human immunodeficiency virus type 1 has several genetic subtypes and two coreceptor use phenotypes: R5 that uses CCR5, while X4 uses CXCR4. A high amino acid charge of the envelope glycoprotein 120 V3 region, common at positions 11 and 25, is important for CXCR4 use. We characterized charged V3 amino acids, retrieving all biologically phenotyped sequences from the HIV Sequence Database. Selecting individually unique ones randomly yielded 48 subtype A, 231 B, 180 C, 37 D and 32 CRF01_AE sequences; 482 were R5 and 46 were X4. Charged amino acids were conserved in both R5 and X4 with general and subtype-specific patterns. X4 viruses gained a higher charge from positive amino acids at positions other than in R5, and through the loss of negative amino acids. Other positions than 11/25 had a greater impact on charge (P,0.001). This describes how R5 evolves into X4 in a subtype-specific context, useful for computer-based predictions and vaccine design.To determine the biological function by the amino acid sequences, generates a need to correctly couple these sequences to the appropriate function. For the highly variable human immunodeficiency virus type 1 (HIV-1), such conformity is crucial.Despite the genetic diversity of HIV-1 in subtypes, subsubtypes and recombinant forms, there are only two major phenotypes for cell entry: R5 and X4 (and dual-tropic R5X4), depending on if the virus uses the chemokine coreceptors CCR5, CXCR4 or both (Berger et al., 1998). Previously, such HIV-1 phenotypes were related to whether the cells were syncytium-inducing (SI) or non-syncytiuminducing (NSI), or expressed macrophage (M-tropic) or Tcell (T-tropic) tropism. These three overlap without being interchangeable (Berger et al., 1998).The NSI phenotype appears early in infection and is related to transmission (Zhu et al., 1993), while the SI is associated with disease progression (Koot et al., 1993). The same has been shown for the R5 and X4 phenotypes (Connor et al., 1997; Scarlatti et al., 1997;Casper et al., 2002).HIV-1 subtypes differ epidemiologically and clinically. Subtype C is the most common. Subtype B has dominated among HIV-1-positive intravenous drug users and men who have sex with men. Subtype D is primarily found in central Africa, where subtype A is also prevalent. Subtype D had a larger proportion of CXCR4-using viruses than subtype A (Huang et al., 2007), and was associated with a faster disease progression than A, B or C (Vasan et al., 2006;Baeten et al., 2007;Kiwanuka et al., 2010; Easterbrook et al., 2010). Circulating recombinant form (CRF) 01_AE is spreading in South-east Asia.The HIV-1 envelope glycoprotein 120 (gp120) third variable region (V3) is important for viral tropism (Hwang et al., 1991). Substitutions of single amino acids within V3 affect the NSI/SI phenotype in subtypes A, B, C, D and CRF01_AE (de Jong et al., 1992b;Fouchier et al., 1992;De Wolf et al., 1994). Positively charged V3 amino acids have been associated with the SI phenotype (de Jong et al., 1992a) and M-tropic viruses with a lower V3 net...

HIV coreceptor tropism determination and mutational pattern identification

“…To date, several studies 12 14 36 37 38 39 40 have reported a key role of the V3 charge in coreceptor tropism. Improved performance has been observed by incorporating the V3 charge rule (11/25 rule and V3 net charge).…”

V3-Independent Competitive Resistance of a Dual-X4 HIV-1 to the CXCR4 Inhibitor AMD3100

“…However, it remains to be determined how CXCR4-using HIV-1 without a positively charged amino acid at the 11th position of the V3 loop escapes from CXCR4 inhibitors. Since higher prevalence of CXCR4-using HIV-1 in CRF01_AE compared to subtype B has been reported [38], we first cloned and sequenced the env regions of HIV-1s from 21 CRF01_AE-infected individuals in a Japanese cohort to find CXCR4-using HIV-1 lacking positively charged amino acids at the 11th and 25th positions of the V3 loop. Among them, two out of five clones isolated from individual KI812 had a unique amino acid sequence (KI812.7) as shown in Fig.…”