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...

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