Original Article

Treatment-Naïve HIV-Infected Patients Have Fewer Gut-Homing β7 Memory CD4 T Cells than Healthy Controls

Authors: Nada Fadul, MD, Jacob Couturier, PhD, Xiaoying Yu, PhD, Claudia Kozinetz, PhD, MPH, Roberto Arduino, MD, Dorothy E. Lewis, PhD


Objectives: The integrin α4β7 is the gut-homing receptor for lymphocytes. It also is an important co-receptor for human immunodeficiency virus (HIV) via glycoprotein (gp)120 binding. Depletion of gut cluster of differentiation (CD)4 T cells is linked to chronic inflammation in patients with HIV; however, measuring CD4 cells in the gut is invasive and not routine. As such, establishing a peripheral marker for CD4 depletion of the gut is needed. We hypothesized that α4β7 CD4 T cells are depleted in the peripheral blood of treatment-naïve patients with HIV compared with healthy controls.

Methods: The study groups were treatment-naïve patients with HIV and uninfected controls. Subjects were included if they were 18 years or older with no history of opportunistic infections, active tuberculosis, or cancer. We collected peripheral blood and examined on whole blood using flow cytometry for the following cell surface markers: CD4, CD45RO, chemokine receptor type 5, C-X-C chemokine receptor type 4 (CXCR4), and the integrin β7. We collected demographic information, including age, sex, and ethnicity, as well as viral load (VL) and CD4 count. Two-sample t tests and Fisher exact tests were used to compare the differences between the two groups. Spearman correlation coefficients were calculated between CD4 count and log10− VL and percentage of CD4+/CD45RO+/β7+ and log10− VL in patients.

Results: Twenty-two subjects were enrolled in the study (12 patients with HIV and 10 controls). There were no differences in age or sex between the two groups. There were more Hispanics and fewer Asians in the group comprising patients with HIV compared with the control group (7 vs 2 and 0 vs 4, P = 0.05, respectively). Patients infected with HIV had significantly lower frequencies of CD4+/CD45RO+/β7+ cells (median 12%, range 5–18 compared with uninfected controls: median 20%, range 11–26, P = 0.0007). There was a statistically significant difference in the percentage of CD4+/CD45RO+/C-X-C chemokine receptor type 4+ cells between patients (72%, range 60%–91%) compared with controls (79%, range 72%–94%, P = 0.04). The percentage of CD4+/CD45RO+/chemokine receptor type 5+ did not differ between the group of patients with HIV and the control groups (22%, range 11%–57% vs 27%, range 14%–31%; P = 0.8, respectively). There was no correlation between percentage of CD4+/CD45RO+/β+ cells and log10− VL as measured by the Spearman correlation coefficient (r = 0.05, P = 0.88) in patients infected with HIV.

Conclusions: Memory CD4 β7+ cells are reduced significantly in the peripheral blood of untreated patients infected with HIV, which could be used as a noninvasive indicator of intestinal CD4 T cell loss and recovery. Further studies are needed to examine whether depletion of these CD4+/CD45RO+/β7+ cells in the peripheral blood parallels depletion in the gut of treatment-naïve patients with HIV and whether levels return to control levels after treatment.

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1. Arthos J, Cicala C, Martinelli E, et al. HIV-1 envelope protein binds to and signals through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol 2008;9:301-309.
2. Cicala C, Arthos J, Fauci AS. HIV-1 envelope, integrins and co-receptor use in mucosal transmission of HIV. J Transl Med 2011;9(suppl 1):S2.
3. McKinnon LR, Nyanga B, Chege D, et al. Characterization of a human cervical CD4+ T cell subset coexpressing multiple markers of HIV susceptibility. J Immunol 2011;187:6032-6042.
4. Nawaz F, Cicala C, Van Ryk D, et al. The genotype of early-transmitting HIV gp120s promotes α (4) β(7)-reactivity, revealing α (4) β(7) +/CD4+ T cells as key targets in mucosal transmission. PLoS Pathog 2011;7:e1001301.
5. Byrareddy SN, Kallam B, Arthos J, et al. Targeting α4β7 integrin reduces mucosal transmission of simian immunodeficiency virus and protects gut-associated lymphoid tissue from infection. Nat Med 2014;20: 1397-1400.
6. Byrareddy SN, Arthos J, Cicala C, et al. Sustained virologic control in SIV+ macaques after antiretroviral and α4β7 antibody therapy. Science 2016;354: 197-202.
7. Krzysiek R, Rudent A, Bouchet-Delbos L, et al. Preferential and persistent depletion of CCR5+ T-helper lymphocytes with nonlymphoid homing potential despite early treatment of primary HIV infection. Blood 2001;98: 3169-3171.
8. Ibarrondo FJ, Wilson SB, Hultin LE, et al. Preferential depletion of gut CD4-expressing iNKT cells contributes to systemic immune activation in HIV-1 infection. Mucosal Immunol 2013;6:591-600.
9. Sousa AE, Carneiro J, Meier-Schellersheim M, et al. CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J Immunol 2002;169:3400-3406.
10. Paiardini M, Muller-Trutwin M. HIV-associated chronic immune activation. Immunol Rev 2013;254:78-101.
11. Wang X, Xu H, Gill AF, et al. Monitoring alpha4beta7 integrin expression on circulating CD4+ T cells as a surrogate marker for tracking intestinal CD4+ T-cell loss in SIV infection. Mucosal Immunol 2009;2:518-526.
12. Mavigner M, Cazabat M, Dubois M, et al. Altered CD4+ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals. J Clin Invest 2012;122:62-69.
13. Cicala C, Martinelli E, McNally JP, et al. The integrin alpha4beta7 forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1. Proc Natl Acad Sci USA 2009;106: 20877-20882.
14. Kader M, Wang X, Piatak M, et al. Alpha4(+)beta7(hi)CD4(+) memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection. Mucosal Immunol 2009;2:439-449.
15. Budde ML, Lhost JJ, Dudley DM, et al. Integrin alpha4beta7 is downregulated on the surfaces of simian immunodeficiency virus SIVmac239-infected cells. J Virol 2010;84:6344-6351.