Variable region 4 of SIV envelope correlates with rapid disease progression in morphine-exposed macaques infected with SIV/SHIV

AIDS Research Program, Ponce School of Medicine, Ponce, PR 00732, Puerto Rico. <>
Virology (Impact Factor: 3.32). 03/2007; 358(2):373-83. DOI: 10.1016/j.virol.2006.08.039
Source: PubMed


We analyzed the association between the evolution of the V3-V5 regions of env and disease progression in our SIV/SHIV macaque model of morphine dependence and AIDS. Previous studies revealed two distinct disease patterns--fast progression and normal progression. To determine the effect of the two distinct patterns of disease in the evolution of SIV/17E-Fr envelope, we analyzed env sequences from three morphine-dependent macaques that developed accelerated AIDS and three morphine-dependent macaques that developed AIDS at a slower rate and compared them to control macaques. Morphine-dependent animals exhibited a higher percentage of diversity in both plasma and CSF compartments within V4 when compared to controls. Divergence from the inoculum was significantly greater in the morphine group as compared to controls in CSF but not in plasma. We also found a direct correlation in V4 evolution and rapid disease progression. These results indicate that morphine dependence plays a role in the pathogenesis of SIV/SHIV infection and env evolution.

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    • "The envelopes isolated from individuals infected with subtype C HIV-1 demonstrated that slow progressors had a significantly longer C3-V4 region compared with progressors [8]. In addition, rapid progressors among SIV-infected macaques exhibited high diversity in the V4 region [9]. Furthermore, neutralization escape has been associated with amino acid substitutions and sequence insertion/deletion in the V4 region in SIV [10], [11] andaqqa HIV infection [12]. "
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    ABSTRACT: The importance of the fourth variable (V4) region of the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein (Env) in virus infection has not been well clarified, though the polymorphism of this region has been found to be associated with disease progression to acquired immunodeficiency syndrome (AIDS). In the present work, we focused on the correlation between HIV-1 gp120 V4 region polymorphism and the function of the region on virus entry, and the possible mechanisms for how the V4 region contributes to virus infectivity. Therefore, we analyzed the differences in V4 sequences along with coreceptor usage preference from CCR5 to CXCR4 and examined the importance of the amino acids within the V4 region for CCR5- and CXCR4-tropic virus entry. In addition, we determined the influence of the V4 amino acids on Env expression and gp160 processing intracellularly, as well as the amount of Env on the pseudovirus surface. The results indicated that V4 tended to have a shorter length, fewer potential N-linked glycosylation sites (PNGS), greater evolutionary distance, and a lower negative net charge when HIV-1 isolates switched from a coreceptor usage preference for CCR5 to CXCR4. The N- and C-terminals of the HIV-1 V4 region are highly conserved and critical to maintain virus entry ability, but only the mutation at position 417 in the context of ADA (a R5-tropic HIV-1 strain) resulted in the ability to utilize CXCR4. In addition, 390L, 391F, 414I, and 416L are critical to maintain gp160 processing and maturation. It is likely that the hydrophobic properties and the electrostatic surface potential of gp120, rather than the conformational structure, greatly contribute to this V4 functionality. The findings provide information to aid in the understanding of the functions of V4 in HIV-1 entry and offer a potential target to aid in the development of entry inhibitors.
    PLoS ONE 01/2014; 9(1):e86083. DOI:10.1371/journal.pone.0086083 · 3.23 Impact Factor
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    • "V4, in contrast to all other regions identified , showed a direct correlation between evolution and morphine-dependent rapid progression (Rivera- Amill et al, 2007). In SIV, V4 has been implicated in determining coreceptor use and that may account for the unique result for this variable region in these rapid progressors (Cho et al, 1998; Hu et al, 2000; Smyth et al, 1998; Rivera-Amill et al, 2007). The V3– V5 analysis was also performed for CSF, where the plasma pattern was reproduced. "
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