Natural Resistance to HIV Infection: Role of Immune Activation

Although repeated exposure to HIV-1 can result in infection, some individuals remain seronegative without clinical or serologic evidence of infection; these individuals are known as HIV-1-exposed seronegative individuals. This population has been extensively studied to understand the mechanisms associated with natural resistance to HIV infection. Two main hypotheses have been proposed to explain this resistance: some researchers associated resistance with a low activation phenotype characterized by a decrease in the activation and proliferation of immune system cells linked with infection control and decreased production of cytokines and pro-inflammatory molecules, whereas others suggest that resistance is related to immune system activation and the expression of high levels of chemokines, pro-inflammatory cytokines and antiviral molecules.

Our study aims to review and analyze the most relevant evidence supporting the role of the activation level of the immune system during natural resistance to HIV-1 infection.

A search was conducted via the PubMed, SciELO and ScienceDirect databases. The literature search was performed in a nonsystematic manner. Articles published in the last five decades addressing immune activation mechanisms in natural resistance to HIV were reviewed.

A low-activation phenotype, characterized by a high frequency of Treg cells; reduced expression of CD25, CD38, and HLA-DR; and lower production of pro-inflammatory cytokines in peripheral and mucosal tissues, plays a key role in reducing the number of activated cells susceptible to infection, but it minimizes chronic inflammation, facilitating viral entry and spread. In contrast, the activation phenotype is associated with high expression of markers such as CD25, CD38, and HLA-DR, along with elevated high levels of interferon-stimulated genes and pro-inflammatory cytokines. This profile could promote infection control while increasing the number of virus-susceptible cells.

The complexity of the immune response during HIV exposure, reflected in the conflicting evidence concerning whether low or high immune activation offers protection against infection, suggests that there may be multiple pathways to HIV-1 resistance, influenced by factors such as the type of viral exposure, the immune environment, and individual genetics. Further research is needed to determine which immune states are protective and how these responses can be modulated to prevent infection.