Vulnerability to reservoir reseeding due to high immune activation after allogeneic hematopoietic stem cell transplantation in individuals with HIV-1

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only medical intervention that has led to an HIV cure. Whereas the HIV reservoir sharply decreases after allo-HSCT, the dynamics of the T cell reconstitution has not been comprehensively described. We analyzed the activation and differentiation of CD4+ and CD8+ T cells, and the breadth and quality of HIV- and CMV-specific CD8+ T cell responses in 16 patients with HIV who underwent allo-HSCT (including five individuals who received cells from CCR5Δ32/Δ32 donors) to treat their underlying hematological malignancy and who remained on antiretroviral therapy (ART). We found that reconstitution of the T cell compartment after allo-HSCT was slow and heterogeneous with an initial expansion of activated CD4+ T cells that preceded the expansion of CD8+ T cells. Although HIV-specific CD8+ T cells disappeared immediately after allo-HSCT, weak HIV-specific CD8+ T cell responses were detectable several weeks after transplant and could still be detected at the time of full T cell chimerism, indicating that de novo priming, and hence antigen exposure, occurred during the time of T cell expansion. These HIV-specific T cells had limited functionality compared with CMV-specific CD8+ T cells and persisted years after allo-HSCT. In conclusion, immune reconstitution was slow, heterogeneous, and incomplete and coincided with de novo detection of weak HIV-specific T cell responses. The initial short phase of high T cell activation, in which HIV antigens were present, may constitute a window of vulnerability for the reseeding of viral reservoirs, emphasizing the importance of maintaining ART directly after allo-HSCT.

Antigen-driven clonal selection shapes the persistence of HIV-1 infected CD4+T cellsin vivo

“…Future research should investigate other ubiquitous pathogens that typically co-infect people living with HIV-1 and commensal microbials that play a role in chronic antigenic stimulation. Moreover, antigen-independent mechanisms that contribute to the reservoir structure need to be explored, such as the proliferation induced by T cell depletion, that occurs upon ART introduction (75) or post-therapeutic ablation (32,76). Similarly, steady-state homeostatic proliferation, which allows the persistence of long-term memory in the absence of antigen, likely plays a role in the maintenance of the HIV-1 reservoir.…”

Brief Report: Rebound HIV Viremia With Meningoencephalitis After Antiretroviral Therapy Interruption After Allogeneic Bone Marrow Transplant

“…Recently, the IciStem Consortium demonstrated incomplete T-cell reconstitution in PLWH following alloBMT, where there could be small yet persistent HIV-specific CD8 + T-cell responses in some individuals. 25 The extent on the potency of these small pools of CD8 + T cells and their ability to prevent serious clinical complications (eg, meningoencephalitis) remain to be investigated. In the Boston patients, there were negligible HIV-specific T-cell responses measured after alloBMT nor during the ATI.…”

So Pathogenic or So What?—A Brief Overview of SIV Pathogenesis with an Emphasis on Cure Research

“…ART does not completely restore the immune system, nor eradicate HIV. Multiple strategies towards an HIV cure are pursued [305][306][307][308][309][310][311][312][313][314][315][316][317][318][319][320][321][322][323], but none effectively curbed the reservoir nor induced robust and durable virus control, except the hematopoietic stem-cell transplantation, which is not scalable and has unreasonable limitations [7,8,324,325]. The major barriers to a successful HIV eradication are: (i) HIV persistence in latently infected cells invisible to immune responses; (ii) inability of a damaged/exhausted immune system to eliminate HIV-infected cells; and (iii) chronic INFL that persists on ART [326][327][328][329][330].…”