CCR5 Expression Is Reduced in Lymph Nodes of HIV Type 1-Infected Women, Compared With Men, But Does Not Mediate Sex-Based Differences in Viral Loads

Meditz, Amie L.; Folkvord, Joy M.; Lyle, Ngan H.; Searls, Kristina; Lie, Yolanda; Coakley, Eoin; McCarter, Martin D.; MaWhinney, Samantha; Connick, Elizabeth

doi:10.1093/infdis/jit575

Cited by 17 publications

(14 citation statements)

References 47 publications

(70 reference statements)

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“…9 In all instances in which virus tropism has been determined in these subjects they were infected with R5 tropic virus. 8 It is unknown whether a similar follicular concentration of virus exists in X4 infections. Intriguingly, studies of SIV-infected rhesus macaques acutely coinfected with R5 and X4 viruses demonstrated that the preference for R5 replication does not exist during acute infection, but only emerges several weeks after infection coincident with the development of virusspecific cytotoxic T cells (CTL), 49 providing support for the hypothesis that it is the adaptive immune response that favors R5 infection over X4 infection.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3][4] While the majority of CD4 + T cells are found within the T cell zones (extrafollicular areas) of lymphoid tissues, most HIV-1-producing cells are CD4 + T cells located within B cell follicles in early and intermediate stages of HIV disease. [5][6][7][8][9] In untreated HIV-1-infected individuals without AIDS, follicular CD4 + cells are 40 times more likely to be productively infected than extrafollicular CD4 + cells. 9 Mechanisms underlying the concentration of HIV-1 replication in follicular CD4 + T cells are not well understood.…”

Section: Introductionmentioning

confidence: 99%

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Distinct Patterns of Bcl-2 Expression Occur in R5- and X4-Tropic HIV-1-Producing Lymphoid Tissue Cells InfectedEx Vivo

Haas

Levy²,

Folkvord

et al. 2015

AIDS Research and Human Retroviruses

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Most HIV-1 replication occurs in secondary lymphoid tissues in T cells within B cell follicles. Mechanisms underlying the accumulation of HIV-1-producing cells at these sites are not understood. Antiapoptotic proteins such as Bcl-2 could promote follicular CD4(+) T cell survival, contributing to sustained virus production. Tonsils obtained from subjects without known HIV infection were disaggregated and analyzed for Bcl-2 expression in follicular (CXCR5(+)) and extrafollicular (CXCR5(-)) CD3(+)CD4(+) cells by flow cytometry. Additional tonsil cells were cultured with phytohemagglutinin (PHA) and interleukin-2 (IL-2) for 2 days, infected with either CCR5(R5) or CXCR4-tropic (X4) GFP reporter viruses, and analyzed for Bcl-2 expression. In freshly disaggregated CD3(+)CD4(+) tonsil cells, mean florescence intensity (MFI) for Bcl-2 was higher in CXCR5(+) (median, 292) compared to CXCR5(-) cells (median, 194; p=0.001). Following in vitro stimulation with PHA and IL-2, Bcl-2 MFI was higher in both CXCR5(+) cells (median, 757; p=0.03) and CXCR5(-) cells (median, 884; p=0.002) in uninfected cultures compared to freshly isolated tonsil cells. Bcl-2 MFI was higher in GFP(+)CD3(+)CD8(-) R5-producing cells (median, 554) than in X4-producing cells (median, 393; p=0.02). Bcl-2 MFI was higher in R5-producing CXCR5(+) cells (median, 840) compared to all other subsets including R5-producing CXCR5(-) cells (median, 524; p=0.04), X4-producing CXCR5(+) cells (median, 401; p=0.02), and X4-producing CXCR5(-) cells (median, 332; p=0.008). Bcl-2 expression is elevated in R5 HIV-1-producing CXCR5(+) T cells in vitro, which may contribute to propagation of R5 virus in B cell follicles in vivo.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Distinct Patterns of Bcl-2 Expression Occur in R5- and X4-Tropic HIV-1-Producing Lymphoid Tissue Cells InfectedEx Vivo

Haas

Levy²,

Folkvord

et al. 2015

AIDS Research and Human Retroviruses

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“…found that women have reduced lymph node CCR5 expression, but this could not account for the lower viral load. Instead, lower viral load in plasma was associated with each HIV‐1 RNA‐producing cell, suggesting that women may either produce fewer virions per productively infected cell, or more effectively clear extracellular virus . Because HIV‐2 is more promiscuous in its coreceptor usage, using coreceptors other than CCR5 , one may expect the biggest sex difference to be seen in HIV‐1‐mono‐infected patients.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of sex in a West African cohort of HIV‐1, HIV‐2 and HIV‐1/2 dually infected patients: men are worse off

Jespersen

Hønge

Esbjörnsson

et al. 2015

Tropical Med Int Health

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Abstractobjectives Several studies have reported conflicting effects of sex on HIV-1 infection. We describe differences in baseline characteristics and assess the impact of sex on HIV progression among patients at a clinic with many HIV-2 and HIV-1/2 dually infected patients.methods This study utilised a retrospective cohort of treatment-na€ ıve adults at the largest HIV clinic in Guinea-Bissau from 6 June 2005 to 1 December 2013. Baseline characteristics were assessed and the patients followed until death, transfer, loss to follow-up, or 1 June 2014. We estimated the time from the first clinic visit until initiation of ART, death or loss to follow-up using Cox proportional hazard models.results A total of 5694 patients were included in the study, 3702 women (65%) and 1992 men (35%). Women were more likely than men to be infected with HIV-2 (19% vs. 15%, P < 0.01) or dually infected with HIV-1/2 (11% vs. 9%, P = 0.02). For all HIV types, women were younger (median 35 vs. 40 years), less likely to have schooling (55% vs. 77%) or to be married (46% vs. 67%), and had higher baseline CD4 cell counts (median 214 vs. 178 cells/ll). Men had a higher ageadjusted mortality rate (hazard rate ratio (HRR) 1.29, 95% confidence interval (CI) 1.09-1.52) and were more often lost to follow-up (HRR 1.27, 95% CI 1.17-1.39).conclusion Significant differences exist between HIV-infected men and women regardless of HIV type. Men seek treatment at a later stage and, despite better socio-economic status, have higher mortality and loss to follow-up than women.

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“…CD4 T-cell counts ranged from 300 to 1,117 cells per mm 3 (median, 542.5 cells per mm 3 ), and plasma viral load ranged from 3.84 to 5.24 log 10 copies per ml (median, 4.53 log 10 copies per ml). Virus tropism was evaluated in all six subjects as previously described (45). In five subjects virus was determined to be R5 tropic, and in the sixth subject tropism could not be determined.…”

Section: Methodsmentioning

confidence: 99%

Follicular Regulatory T Cells Are Highly Permissive to R5-Tropic HIV-1

Miller

Brodie

Guo

et al. 2017

J Virol

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Follicular regulatory T (TFR) cells are a subset of CD4 T cells in secondary lymphoid follicles. TFR cells were previously included in the follicular helper T (TFH) cell subset, which consists of cells that are highly permissive to HIV-1. The permissivity of TFR cells to HIV-1 is unknown. We find that TFR cells are more permissive than TFH cells to R5-tropic HIV-1 TFR cells expressed more CCR5 and CD4 and supported higher frequencies of viral fusion. Differences in Ki67 expression correlated with HIV-1 replication. Inhibiting cellular proliferation reduced Ki67 expression and HIV-1 replication. Lymph node cells from untreated HIV-infected individuals revealed that TFR cells harbored the highest concentrations of HIV-1 RNA and highest levels of Ki67 expression. These data demonstrate that TFR cells are highly permissive to R5-tropic HIV-1 both and This is likely related to elevated CCR5 levels combined with a heightened proliferative state and suggests that TFR cells contribute to persistent R5-tropic HIV-1 replication In chronic, untreated HIV-1 infection, viral replication is concentrated in secondary lymphoid follicles. Within secondary lymphoid follicles, follicular helper T (TFH) cells have previously been shown to be highly permissive to HIV-1. Recently, another subset of T cells in secondary lymphoid follicles was described, follicular regulatory T (TFR) cells. These cells share some phenotypic characteristics with TFH cells, and studies that showed that TFH cells are highly permissive to HIV-1 included TFR cells in their definition of TFH cells. The permissivity of TFR cells to HIV-1 has not previously been described. Here, we show that TFR cells are highly permissive to HIV-1 both and The expression of Ki67, a marker of proliferative capacity, is predictive of expression of viral proteins, and downregulating Ki67 leads to concurrent decreases in expression of viral proteins. Our study provides new insight into HIV-1 replication and a potential new cell type to target for future treatment.

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CCR5 Expression Is Reduced in Lymph Nodes of HIV Type 1-Infected Women, Compared With Men, But Does Not Mediate Sex-Based Differences in Viral Loads

Cited by 17 publications

References 47 publications

Distinct Patterns of Bcl-2 Expression Occur in R5- and X4-Tropic HIV-1-Producing Lymphoid Tissue Cells InfectedEx Vivo

Distinct Patterns of Bcl-2 Expression Occur in R5- and X4-Tropic HIV-1-Producing Lymphoid Tissue Cells InfectedEx Vivo

Differential effects of sex in a West African cohort of HIV‐1, HIV‐2 and HIV‐1/2 dually infected patients: men are worse off

Follicular Regulatory T Cells Are Highly Permissive to R5-Tropic HIV-1

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