Independent evolution of macrophage-tropism and increased charge between HIV-1 R5 envelopes present in brain and immune tissue

Gonzalez-Perez, Maria Paz; O’Connell, Olivia; Lin, Rongheng; Sullivan, Wendy; Bell, Jeanne E.; Simmonds, Peter; Clapham, Paul R.

doi:10.1186/1742-4690-9-20

Cited by 44 publications

(64 citation statements)

References 86 publications

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“…1a). Previous studies have reported that M-tropic variants are also more sensitive to sCD4 than T-tropic variants (27)(28)(29). We confirmed this observation by showing that M-tropic variants were on average 27-fold more sensitive to sCD4 than their T-tropic counterparts (Fig.…”

Section: Discussionsupporting

confidence: 80%

“…Differences in how macrophage tropism is defined can lead to substantially different observations about M-tropic viruses. Although it is widely observed that M-tropic viruses are able to enter more efficiently at low CD4 densities (14,19,(22)(23)(24)(25)(26) and are more sensitive to neutralization by soluble CD4 (sCD4) (27)(28)(29) than T-tropic viruses, few other characteristics are widely agreed upon. Similarly, several amino acid changes in the HIV-1 Env protein have been associated with macrophage tropism (24,25,27,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39), but the changes are not consistent across different subjects when macrophage tropism is defined as a distinct set of evolutionary variants within that subject (40).…”

mentioning

confidence: 99%

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Phenotypic Correlates of HIV-1 Macrophage Tropism

Arrildt

LaBranche

Joseph

et al. 2015

J Virol

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HIV-1 is typically CCR5 using (R5) and T cell tropic (T-tropic), targeting memory CD4؉ T cells throughout acute and chronic infections. However, viruses can expand into alternative cells types. Macrophage-tropic (M-tropic) HIV-1 variants have evolved to infect macrophages, which have only low levels of surface CD4. Most M-tropic variants have been isolated from the central nervous system during late-stage chronic infection. We used the HIV-1 env genes of well-defined, subject-matched M-tropic and T-tropic viruses to characterize the phenotypic features of the M-tropic Env protein. We found that, compared to T-tropic viruses, M-tropic viruses infect monocyte-derived macrophages (MDMs) on average 28-fold more efficiently, use low-density CD4 more efficiently, have increased sensitivity to soluble CD4 (sCD4), and show trends toward sensitivity to some CD4 binding site antibodies but no difference in sensitivity to antibodies targeting the CD4-bound conformation. M-tropic viruses also displayed a trend toward resistance to neutralization by monoclonal antibodies targeting the V1/V2 region of Env, suggesting subtle changes in Env protein conformation. The paired M-and T-tropic viruses did not differ in autologous serum neutralization, temperature sensitivity, entry kinetics, intrinsic infectivity, or Env protein incorporation. We also examined viruses with modestly increased CD4 usage. These variants have significant sensitivity to sCD4 and may represent evolutionary intermediates. CD4 usage is strongly correlated with infectivity of MDMs over a wide range of CD4 entry phenotypes. These data suggest that emergence of M-tropic HIV-1 includes multiple steps in which a phenotype of increased sensitivity to sCD4 and enhanced CD4 usage accompany subtle changes in Env conformation. IMPORTANCE HIV-1 typically replicates in CD4؉ T cells. However, HIV-1 can evolve to infect macrophages, especially within the brain. Understanding how CCR5-using macrophage-tropic viruses evolve and differ from CCR5-using T cell-tropic viruses may provide insights into viral evolution and pathogenesis within the central nervous system. We characterized the HIV-1 env viral entry gene from subject-matched macrophage-tropic and T cell-tropic viruses to identify entry features of macrophage-tropic viruses. We observed several differences between T cell-tropic and macrophage-tropic Env proteins, including functional differences with host CD4 receptor engagement and possible changes in the CD4 binding site and V1/V2 region. We also identified viruses with phenotypes between that of "true" macrophage-tropic and T cell-tropic viruses, which may represent evolutionary intermediates in a multistep process to macrophage tropism. HIV-1 host cell entry is determined solely by the virion surface protein Env. The Env protein precursor gp160 is cleaved into two proteins: the external gp120 protein and the membrane-spanning gp41 protein, which remain associated as a heterodimer and form trimers of these heterodimers. Attachment of gp120 to the host CD4 ...

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Section: Discussionsupporting

confidence: 80%

mentioning

confidence: 99%

Phenotypic Correlates of HIV-1 Macrophage Tropism

Arrildt

LaBranche

Joseph

et al. 2015

J Virol

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“…We confirmed the role of N283 in macrophage-tropic Env (12,37). However, the identification of many macrophage-tropic Envs that lack N283 (and non-macrophagetropic Envs with N283) indicates that other determinants play a significant role (13,19). We identified complex determinants that included residues on the N-terminal flank of the CD4 binding loop as well as changes in the glycan shield that may affect the exposure of CD4 contact residues (37,38).…”

supporting

confidence: 57%

“…Where possible, we included groups of Envs that had been amplified from single individuals and that included both macrophage-tropic and non-macrophage-tropic Envs. Mainly, we used a panel of Envs that we had previously studied (11) and included more recently amplified and characterized Envs (19 rions were titrated on HeLa TZM-BL cells, which carry ␤-galactosidase and luciferase reporter genes controlled by HIV long terminal repeat (LTR) promoters (46). Infected cells were visualized at 48 h after infection as focus-forming units (FFU) following staining for ␤-galactosidase activity.…”

Section: Methodsmentioning

confidence: 99%

“…This variation results mainly from differences in the ability of HIV-1 to exploit low levels of CD4 on macrophages for infection (10,12,14,15). Recent studies reported that founder viruses transmitted either sexually (16, 17) or via mother to child (18) were non-macrophage-tropic and that they persist in immune tissue even in late disease (10,12,19). Nevertheless, highly macrophage-tropic R5 variants are increasingly detected in late disease (20)(21)(22) and are predominant in brain tissue of subjects with HIV-associated neurocognitive disorders (7,10,12,14).…”

mentioning

confidence: 99%

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Efficiency of Bridging-Sheet Recruitment Explains HIV-1 R5 Envelope Glycoprotein Sensitivity to Soluble CD4 and Macrophage Tropism

O’Connell

Repik

Reeves³

et al. 2013

J Virol

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h HIV-1 R5 viruses vary extensively in their capacity to infect macrophages. R5 viruses that confer efficient infection of macrophages are able to exploit low levels of CD4 for infection and predominate in brain tissue, where macrophages are a major target for infection. HIV-1 R5 founder viruses that are transmitted were reported to be non-macrophage-tropic. Here, we investigated the sensitivities of macrophage-tropic and non-macrophage-tropic R5 envelopes to neutralizing antibodies. We observed striking differences in the sensitivities of Env ؉ pseudovirions to soluble CD4 (sCD4) and to neutralizing monoclonal antibodies (MAbs) that target the CD4 binding site. Macrophage-tropic R5 Envs were sensitive to sCD4, while non-macrophage-tropic Envs were significantly more resistant. In contrast, all Envs were sensitive to VRC01 regardless of tropism, while MAb b12 conferred an intermediate neutralization pattern where all the macrophage-tropic and about half of the non-macrophage-tropic Envs were sensitive. CD4, b12, and VRC01 share binding specificities on the outer domain of gp120. However, these antibodies differ in their ability to induce conformational changes on the trimeric envelope and in specificity for residues on the V1V2 loop stem and ␤20-21 junction that are targets for CD4 in recruiting the bridging sheet. These distinct specificities of CD4, b12, and VRC01 likely explain the observed differences in Env sensitivity to inhibition by these reagents and provide an insight into the envelope mechanisms that control macrophage tropism. We present a model where the efficiency of bridging-sheet recruitment by CD4 is a major determinant of HIV-1 R5 envelope sensitivity to soluble CD4 and macrophage tropism. Human immunodeficiency virus type 1 (HIV-1) entry into cells involves interactions with CD4 and coreceptor CCR5 or CXCR4 to trigger fusion of the virus and cell membranes. In vivo, HIV-1 infection is limited mainly to cells expressing CD4 and an appropriate coreceptor. These include T cells, macrophages, and dendritic cells as well as their progenitors (1-3). In the past, HIV-1 R5 viruses that use CCR5 were described as macrophage-tropic or M-tropic, reflecting a view that such viruses infect macrophages in addition to T cells (4-6). However, studies from our group and others have shown that R5 viruses vary extensively in their capacity to infect macrophages (7-14). This variation results mainly from differences in the ability of HIV-1 to exploit low levels of CD4 on macrophages for infection (10,12,14,15). Recent studies reported that founder viruses transmitted either sexually (16, 17) or via mother to child (18) were non-macrophage-tropic and that they persist in immune tissue even in late disease (10,12,19). Nevertheless, highly macrophage-tropic R5 variants are increasingly detected in late disease (20)(21)(22) and are predominant in brain tissue of subjects with HIV-associated neurocognitive disorders (7,10,12,14).The HIV-1 envelope glycoprotein is a trimer comprising three copies each of gp120 and tran...

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