Long-term antiretroviral treatment initiated at primary HIV-1 infection affects the size, composition, and decay kinetics of the reservoir of HIV-1-infected CD4 T cells

Abstract

Initiation of antiretroviral therapy during the earliest stages of HIV-1 infection may limit the seeding of a long-lasting viral reservoir, but long-term effects of early antiretroviral treatment initiation remain unknown. Here, we analyzed immunological and virological characteristics of nine patients who started antiretroviral therapy at primary HIV-1 infection and remained on suppressive treatment for >10 years; patients with similar treatment duration but initiation of suppressive therapy during chronic HIV-1 infection served as controls. We observed that independently of the timing of treatment initiation, HIV-1 DNA in CD4 T cells decayed primarily during the initial 3 to 4 years of treatment. However, in patients who started antiretroviral therapy in early infection, this decay occurred faster and was more pronounced, leading to substantially lower levels of cell-associated HIV-1 DNA after long-term treatment. Despite this smaller size, the viral CD4 T cell reservoir in persons with early treatment initiation consisted more dominantly of the long-lasting central-memory and T memory stem cells. HIV-1-specific T cell responses remained continuously detectable during antiretroviral therapy, independently of the timing of treatment initiation. Together, these data suggest that early HIV-1 treatment initiation, even when continued for >10 years, is unlikely to lead to viral eradication, but the presence of low viral reservoirs and durable HIV-1 T cell responses may make such patients good candidates for future interventional studies aiming at HIV-1 eradication and cure.

Importance: Antiretroviral therapy can effectively suppress HIV-1 replication to undetectable levels; however, HIV-1 can persist despite treatment, and viral replication rapidly rebounds when treatment is discontinued. This is mainly due to the presence of latently infected CD4 T cells, which are not susceptible to antiretroviral drugs. Starting treatment in the earliest stages of HIV-1 infection can limit the number of these latently infected cells, raising the possibility that these viral reservoirs are naturally eliminated if suppressive antiretroviral treatment is continued for extremely long periods of time. Here, we analyzed nine patients who started on antiretroviral therapy within the earliest weeks of the disease and continued treatment for more than 10 years. Our data show that early treatment accelerated the decay of infected CD4 T cells and led to very low residual levels of detectable HIV-1 after long-term therapy, levels that were otherwise detectable in patients who are able to maintain a spontaneous, drug-free control of HIV-1 replication. Thus, long-term antiretroviral treatment started during early infection cannot eliminate HIV-1, but the reduced reservoirs of HIV-1 infected cells in such patients may increase their chances to respond to clinical interventions aiming at inducing a drug-free remission of HIV-1 infection.

FIG 1

Long-term antiretroviral therapy initiated in primary HIV-1 infection reduces the viral reservoir to levels seen in elite controllers. (A) Trajectories of CD4 T cell counts and CD4/CD8 ratio with 95% pointwise confidence intervals bands in patients with treatment initiation in early (n = 9) versus chronic (n = 16) infection. (B) Copies per cell of total, 2-LTR, and integrated HIV-1 DNA in CD4 T cells isolated from individuals started on suppressive antiretroviral therapy in early HIV-1 infection (ET) and chronic HIV-1 infection (CT) and from elite controllers (EC). Study patients had undetectable viremia for >8 years (EC) or >10 years (ET and CT). (C) Correlation between time from HIV-1 acquisition to antiretroviral treatment initiation and viral reservoir size after 10 years of continuous antiretroviral therapy in HIV-1 patients with treatment initiation in primary HIV-1 infection. (D) Levels of CD4 T cell-associated HIV-1 RNA in the indicated study groups.

FIG 2

Reduced frequencies of CD4 T cells with replication-competent HIV-1 after long-term antiretroviral therapy initiated in primary HIV-1 infection. (A) Infectious units per million CD4 T cells (IUPM) isolated from the study subjects after 10 years of antiretroviral therapy initiated during early (ET) or chronic (CT) HIV-1 infection and from elite controllers (EC). (B) Spearman correlation between the frequencies and corresponding levels of HIV-1 DNA per CD4 T cell. All data pairs with detectable IUPM and total HIV-1 DNA data were included. Open symbols reflect test results below detection threshold.

FIG 3

Antiretroviral treatment initiation in primary HIV-1 infection accelerates HIV-1 DNA decay. (A) Longitudinal evolution of copies per cell of total, 2-LTR, and integrated HIV-1 DNA in CD4 T cells from patients with antiretroviral treatment initiation in early (ET) (n = 9) or chronic (CT) (n = 16) HIV-1 infection. (B) Longitudinal decline of HIV-1 DNA after antiretroviral treatment initiation in primary HIV-1 infection, stratified according to treatment commencement before HIV-1 seroconversion (Fiebig stage III-IV) (n = 3) or after HIV-1 seroconversion (Fiebig stage V) (n = 6). Data are pointwise maximum-likelihood estimates of the means and 95% confidence interval estimates of the mean.

FIG 4

Differential composition of the HIV-1 CD4 T cell reservoir in patients started on antiretroviral treatment in early versus chronic HIV-1 infection. (A) Per-cell levels of total HIV-1 DNA in isolated naive (T_NA), memory stem cell (T_SCM), central-memory (T_CM), effector memory (T_EM), and terminally differentiated (T_TD) CD4 T cells in persons with treatment initiation in early versus chronic HIV-1 infection. (B) Contribution of individual CD4 T cell subsets to the total CD4 T cell pool (top) and to the total HIV-1 CD4 T cell reservoir (bottom) in patients with treatment initiation in early (n = 8) versus chronic (n = 9) HIV-1 infection. The sizes of the pie charts in the lower panel correspond to the smaller size of the total HIV-1 reservoir in CD4 T cells from individuals with early HIV-1 treatment initiation. All measurements were performed with samples after a median of 10 years after treatment initiation.

FIG 5

Long-term persistence of HIV-1-specific T cell responses despite suppressive antiretroviral therapy. The proportion of IFN-γ-secreting HIV-1-specific CD4 (A) and CD8 (B) T cells with the naive, central-memory, effector memory, or terminally differentiated phenotype from elite controllers and individuals with antiretroviral treatment initiation in primary or chronic HIV-1 infection is shown.