Transient Mobilization of Human Immunodeficiency Virus (HIV)-Specific CD4 T-Helper Cells Fails To Control Virus Rebounds during Intermittent Antiretroviral Therapy in Chronic HIV Type 1 Infection

Abstract

Immune control of human immunodeficiency virus (HIV) is not restored by highly active antiretroviral therapies (HAART) during chronic infection.We examined the capacity of repeated structured therapeutic interruptions (STI) to restore HIV-specific CD4 and CD8 T-cell responses that controlled virus production. Eleven STI (median duration, 7 days; ranges, 4 to 24 days) were performed in three chronically HIV-infected patients with CD4 counts above 400/mm 3 and less than 200 HIV RNA copies/ml after 18 to 21 months of HAART; treatment resumed after 1 week or when virus became detectable. HIV-specific T-cell responses were analyzed by proliferation, gamma interferon (IFN-␥) production, and enzyme-linked immunospot assays. Seven virus rebounds were observed (median, 4,712 HIV-1 RNA copies/ml) with a median of 7 days during which CD4 and CD8 counts did not significantly change. After treatment resumed, the viral load returned below 200 copies/ml within 3 weeks. Significant CD4 T-cell proliferation and IFN-␥ production against HIV p24 appeared simultaneously with or even before the virus rebounds in all patients. These CD4 responses lasted for less than 3 weeks and disappeared before therapeutic control of the virus had occurred. Increases in the numbers of HIV-specific CD8 T cells were delayed compared to changes in HIV-specific CD4 T-cell responses. No delay or increase in virus doubling time was observed after repeated STI. Iterative reexposure to HIV during short STI in chronically infected patients only transiently mobilized HIV-specific CD4 T1-helper cells, which might be rapidly altered by virus replication. Such kinetics might explain the failure at delaying subsequent virus rebounds and raises concerns about strategies based on STI to restore durable HIV-specific T-cell responses in chronic HIV infection.

Structured treatment interruptions (STIs) in HIV-1 infected pediatric populations increases interferon gamma production and reduces viremia

“…HIV-specific lymphoproliferative response as measure by the median stimulation index (SI) increased in the treatment group from 1 at baseline to 16,12,4, and 3 at cycles 7, 10, 13, and 17, respectively. The lymphoproliferative SI response in the control group was 6 at baseline and hovered below this level for all visits to week 132 with one exception.…”

“…STI effects were usually assessed by surrogate immunologic studies or by indefinitely suspending antiretrovirals and determining viral setpoint change. This has met with limited success, usually a delay in the rebound of virus after several interruptions (5)(6)(7)(8)(9)(10)(11)(12). A study of STI performed in individuals treated with HAART soon after primary infection found better CD4 T cell-mediated anti-HIV activity and longevity and reduced viral set point (13) but also met with limited success over time (14).…”

Immunological Responses and Long-Term Treatment Interruption after Human Immunodeficiency Virus Type 1 (HIV-1) Lipopeptide Immunization of HIV-1-Infected Patients: the LIPTHERA Study

“…Structured treatment interruption has been explored as a means of offsetting the complexity and toxicity of antiretroviral treatment, and also the development of viral resistance (6,23,34,46). Previous reports suggest that CD4 ϩ T-cell counts are predictive of the outcome after treatment discontinuation (29,36,44,45), even if HAART interruption consistently leads to a fall in the CD4 ϩ T-cell count and to pVL rebound (10,28,30,49).…”

“…Numbers of spot-forming cells (SFCs) were normalized to 10 6 PBMCs and averaged from duplicate wells. The number of specific SFCs per 10 6 PBMCs was calculated by subtracting the negative control value from the experimental SFC count. A CD8 ϩ T-cell response was considered significant when (i) a minimum of 100 SFCs/10 6 PBMCs were present per well, (ii) this number was Ն2 times that obtained with the negative control (PBMCs alone), (iii) the number of SFCs in stimulated wells (with peptide) minus the number of SFCs in unstimulated wells was Ն100/10 6 PBMCs, and (iv) this was true for both duplicates, as described elsewhere (21,51).…”

“…However, HAART also drives the production of HIV antigens below the threshold required to efficiently stimulate HIV-specific T-cell effectors or HIV-specific naive cells (24). Approaches aimed at enhancing anti-HIV immunity include adoptive therapy, cytokine therapy, and therapeutic immunization combined with structured treatment interruption (STI) (6,17).…”