Asymptomatic HIV-infected Individuals on Antiretroviral Therapy Exhibit Impaired Lung CD4⁺T-Cell Responses to Mycobacteria

Abstract

Rationale: HIV-infected persons on antiretroviral therapy (ART) remain at higher risk of pulmonary tuberculosis (TB) than HIV-uninfected individuals. This increased susceptibility may be caused by impairment of alveolar macrophage (AM) function and/or mycobacteria-specific alveolar CD4 1 T-cell responses observed in HIV-infected ART-naive adults.Objectives: To determine whether ART was associated with improvement in both AM function, assessed by phagosomal proteolysis, and alveolar CD4 1 T-cell responses to Mycobacterium in HIV-infected individuals.Methods: Peripheral blood was drawn and bronchoalveolar lavage (BAL) performed on healthy, 35 HIV-uninfected, 25 HIV-infected ART-naive, and 50 HIV-infected ART-treated asymptomatic adults. Phagosomal proteolysis of AM was assessed with fluorogenic beads. Mycobacteria-specific CD4 1 T-cell responses were measured by intracellular cytokine staining.Measurements and Main Results: HIV-infected adults on ART exhibited lower plasma HIV viral load and higher blood CD4 1 T-cell count than ART-naive adults. AM proteolysis and total mycobacteria-specific Th1 CD4 1 T-cell responses in individuals on ART for greater than or equal to 4 years were similar to HIVuninfected control subjects but those on ART for less than 4 years had impaired responses. Total influenza-specific alveolar Th1 CD4 1 Tcell responses were intact in all individuals receiving ART. In contrast, BAL and blood mycobacteria-specific polyfunctional CD4 1 T-cell responses were impaired in adults on ART irrespective of duration.Conclusions: AM and mycobacteria-specific alveolar CD4 1 T-cell responses in HIV-infected adults on ART for less than 4 years are impaired and may partly explain the high risk of TB in HIV-infected individuals on ART. Strategies to augment ART to improve lung immune cell function and reduce the high incidence of TB in HIVinfected adults who initiate ART should be investigated.

Restoration of CD4+ Responses to Copathogens in HIV-Infected Individuals on Antiretroviral Therapy Is Dependent on T Cell Memory Phenotype

“…Several additional CD4+ T cell subsets and cytokines contribute to TB immunity (61-64), and we have found an even greater diversity of CD4+ T cell subsets specific for Mtb (Riou et al, submitted for publication). An additional issue is that we do not know the extent of pathogen-specific CD4+ recovery in tissues upon ART, which appears defective for TB in the lungs even after prolonged viral suppression (20). These considerations may account for the persistently greater susceptibility of successfully treated HIV-infected individuals to TB (65).…”

“…Although the clinical benefit of ART is undeniable, the extent to which ART can fully “normalize” functional immunity remains unclear (13). HIV-infected individuals on ART exhibit a differential degree of recovery of co-pathogen-specific CD4+ T cell responses, depending on the pathogen they target (14-20). For example, it has been shown that the restoration of CMV-specific CD4+ T cells occurs early after ART (19), but appears to be short-lived (15).…”

“…Contrasting data exist on the degree of recovery of Mycobacterium tuberculosis (Mtb)-specific CD4+ T cell responses upon ART. Jambo et al showed in a cross-sectional study that the frequency and polyfunctional profile of Mtb-specific CD4+ T cell responses were similar in ART-naïve or treated individuals (20), while Sutherland et al reported that ART increases the polyfunctional capacity of these cells (18). Other studies described only a partial reconstitution of Mtb-specific CD4+ T cell responses after ART (14, 17).…”

Relationship Between HIV Coinfection, Interleukin 10 Production, andMycobacterium tuberculosisin Human Lymph Node Granulomas

“…HIV–mediated destruction of CD4 + T cells is important to tuberculosis pathology because these cells are necessary for the appropriate response to M. tuberculosis [4, 5]. HIV also leads to a reduction in ex vivo peripheral [6, 7] and airway [8, 9] T-cell cytokine production following M. tuberculosis antigen stimulation. HIV infection has also been shown in vitro to increase the growth of M. tuberculosis in coinfected macrophages [10, 11], but such responses are highly variable [12].…”

Early initiation of antiretroviral treatment: Challenges in the Middle East and North Africa

“…Feasibility of early initiation of ART in MENA in the two groups, with migrants from MENA displaying significantly higher rates of TB in the first year after initiation of ART [15] . Immune response to tuberculosis is blunted following ART initiation, and this suppression persists for years due to decreased alveolar macrophage activity and specific cellular responses [43] . Hence, patients that receive ART remain susceptible to TB, a challenge that requires further attention in TB endemic countries of MENA.…”