Platelets Target the Circulating HIV Reservoir: Implications for Immunological Failure

Condition(s) studied

Investigational drug(s) / intervention(s)

blood sampling: During a routine consultation, a specific 40 mL blood sample will be collected for the study.

Study summary

HIV/AIDS is a chronic disease that is difficult to eradicate because the virus persists as proviral DNA integrated into the host cells. Despite antiretroviral therapy, proviral DNA persists in lymphoid and myeloid reservoirs, whether circulating (memory CD4+ T cells) or tissue-based (macrophages). HIV reservoirs are highly heterogeneous, making it difficult to identify a specific biomarker or cell profile for a given reservoir. A distinctive feature of HIV reservoirs may be the selective interaction between reservoir cells and platelets. The presence of HIV in platelets could impact disease progression, particularly by triggering the reversal of HIV latency and leading to residual viral production. The frequency of platelets containing circulating virus in the blood is approximately 0.1% of the total platelet volume. Although seemingly negligible, this would represent a daily input of 10⁸ platelets harboring the virus. Furthermore, patients whose platelets contain HIV are primarily those with persistent immunological failure, known as "immunological non-responders" (InR).

The regulation of the size (number and frequency) of the HIV reservoir by platelets is not known. However, HIV-containing platelets form more conjugates with CD4+ T cells than HIV-free platelets. While HIV-containing platelets do not productively infect cells, they induce metabolic dysfunction in CD4+ T cells (aerobic glycolysis). Increased aerobic glycolysis is a hallmark of T cell activation and senescence.

This suggests an interconnection between the presence of the virus in platelets, the size of the reservoir, and immune dysfunction in HIV.

Eligibility

Primary outcome measure(s)

• In vivo evaluation of the formation of platelet-PBMC conjugates enriched in latent or active reservoirs and of their transcriptional competence — at enrollment
  In vivo evaluation of the formation of platelet-PBMC conjugates enriched in latent or active reservoirs, correlated with immune status through the following parameters: Frequency of CD4+ T lymphocytes associated with platelets and/or platelet components, Frequency of platelet-associated CD4+ T cells carrying HIV RNA, and ex vivo HIV reactivation; Number of integrated HIV provirus copies in CD4+ T cells associated or not with platelets. Monitoring of the transcriptional competence of platelet-associated reservoirs ex vivo, and the capacity of platelets to reactivate these reservoirs (latency reversal) in vitro based on the following criterion: Frequency of J-Lat GFP+ cells (indicating a reactivated provirus in this reporter cell) after coculture with platelets obtained from individuals of the different experimental groups.

Trial sites (1)

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