Evolution and Diversity of Immune Responses during Acute HIV Infection

Abstract

Understanding the earliest immune responses following HIV infection is critical to inform future vaccines and therapeutics. Here, we review recent prospective human studies in at-risk populations that have provided insight into immune responses during acute infection, including additional relevant data from non-human primate (NHP) studies. We discuss the timing, nature, and function of the diverse immune responses induced, the onset of immune dysfunction, and the effects of early anti-retroviral therapy administration. Treatment at onset of viremia mitigates peripheral T and B cell dysfunction, limits seroconversion, and enhances cellular antiviral immunity despite persistence of infection in lymphoid tissues. We highlight pertinent areas for future investigation, and how application of high-throughput technologies, alongside targeted NHP studies, may elucidate immune response features to target in novel preventions and cures.

Keywords: HIV; SIV; acute infection; host-pathogen.

Figure 1.. Acute HIV infection dynamics.

(A) Representative dynamics of plasma viral load and peripheral CD4⁺ T cell counts during acute HIV infection. Individuals that develop control of HIV without ART can maintain low chronic viral setpoint and reestablish pre-infection CD4⁺ T cell levels (Elite or Viremic Controllers). Individuals and animals can also maintain high chronic viral setpoint but also recover CD4⁺ T cell counts (Long-Term Non-Progressors [LTNP], and natural hosts, respectively). (B) Representative immune responses and their timing along the course of acute HIV infection. Without structured cohorts to reliably sample before Fiebig Stage I, the earliest responses are inferred from SIV/SHIV models and limited human studies. (C) Cellular and molecular factors in AHI that contribute to disease progression or control. The progression-control spectrum has been linked to the magnitude, timing, and function of several distinct immune responses. Box colors represent different cell types or cytokine responses.

Figure 2.. Known and inferred immune cell signaling during untreated acute HIV infection.

Understanding the interplay between distinct immune subsets in acute HIV infection is essential to disentangle the effects of key cytokines (e.g. Type I and II interferons, IL-10, IL-17, etc.) on each cell type. Moreover, realizing the compartment specific responses and their effects will allow for more targeted treatment. Experimentally measured interactions are depicted with solid arrows. Interactions for which only the signaler or receiver has been measured are shown by arrows with hybrid solid and dashed lines, which are inferred from literature on chronic infection or other models. The supporting assay for each interaction is listed with each cytokine or factor. GZMB = granzyme B; PRF1 = perforin; WB = Western Blot; RNA = RNA-sequencing; FC = Flow Cytometry; ELISA = Enzyme-linked Immunosorbent Assay; Lum = Luminex Multiplex Assay; CoC = in vitro coculture.

Figure 3.. Effects of early ART administration during acute HIV infection on peripheral and tissue immune responses.

We are just beginning to understand the effects of early ART on AHI with improved NHP models and cohorts treating at HIV-detection throughout Fiebig Stages I-III. Overall, early ART mitigates peripheral cytokine production and adaptive immune cell dysfunction. Samples from early ART treated individuals in prospective cohorts provide a unique opportunity to explore similarities and differences in cellular response and phenotype across tissue compartments. Whether we can use our understanding of these improved antiviral responses to inform long-term cure strategies or vaccines is still unknown. Abs = antibodies; HPC = hematopoietic precursor cell.