The Initial Viral Infection and Lack of a Vigorous Pro-Inflammatory Response Against the Virus

Natural Resistance to HIV Infection

It is well established that many individuals exposed to HIV never become infected. This group includes sex workers, children born to HIV-positive mothers, and individuals frequently engaging in high-risk sexual behavior. If HIV can sometimes be cleared from the body, why doesn’t this occur more routinely?

The Role of CD8+ T Cells and Suppressor Factors

Mounting research suggests that cytotoxic CD8+ T cells play a central role in regulating CD4+ T cell decline. Individuals with the slowest CD4 loss tend to have the highest levels of CD8+ cytotoxic cells in their blood. While direct killing is one method of viral control, CD8+ cells also release suppressor factors that reduce the ability of CD4+ cells to produce or be infected by HIV.

In a study of 25 high-risk but uninfected individuals, CD4+ cells showed reduced susceptibility to infection by primary HIV isolates compared to a control group with no prior exposure. The CD8+ cells in these individuals secreted pro-inflammatory chemokines such as RANTES, MIP-1α, and MIP-1β.

IL-16: A Critical Immune Modulator

CD8+ cells also produce IL-16, which inhibits HIV replication in lymphocytes, monocytes, and dendritic cells by repressing viral transcription. Effective against both lab-adapted and natural viral strains, IL-16 levels decrease as HIV symptoms progress. Crucially, IL-16 induces CD25 expression—the IL-2 receptor—on naïve CD4+ cells, priming them to respond to IL-2. Together, IL-2 and IL-16 promote CD4+ expansion in culture and are under consideration as potential therapies to restore immune function in HIV-infected patients.

Interestingly, serotonin, a neurotransmitter with broad biological roles, stimulates IL-16 synthesis and release from CD8+ cells—one mechanism by which serotonin activates cell-mediated immunity.

Inflammation as a Defense Mechanism

For CD8+ T cells to eliminate infected targets, they must first locate sites of infection. This process is mediated by inflammation. Pro-inflammatory chemokines, such as MIP-1α secreted by macrophages and T cells, attract cytotoxic T cells to infected tissues—like the lungs during influenza or the anal and vaginal mucosa in HIV.

In mice lacking MIP-1α, influenza infection reduces inflammation and poor viral clearance. Without MIP-1α, immune cells cannot effectively home to infected tissue. This raises a question: why doesn’t a similar inflammatory response routinely occur in mucosal tissues exposed to HIV? Documented cases show the virus can be cleared—so why is this the exception?

Glucocorticoids, Stress, and Immunosuppression

Stress and its accompanying release of glucocorticoids, particularly hydrocortisone, may be a key factor. Hydrocortisone inhibits the production of chemokines like RANTES, MIP-1α/β, MIP-2, and IL-8, thereby impairing the recruitment of T cells, monocytes, eosinophils, and neutrophils to infection sites. Elevated glucocorticoid levels under chronic stress might thus prevent effective immune activation and viral clearance.

Additionally, viral proteins such as VPR, TAT, NEF, and gp120 further contribute to immunosuppression. VPR is present in every viral particle—infectious or not—and binds a host protein that activates the glucocorticoid receptor. This VPR-glucocorticoid complex enters the nucleus and modulates gene expression, suppressing immune responses. Drugs like RU-486, which block glucocorticoid receptor activation, can inhibit VPR’s effects.

Synergistic Effects of Viral Proteins and Hormones

Hydrocortisone can also enhance the synthesis of TGF-β, another potent immunosuppressive factor. Its production may be upregulated by viral proteins like TAT, gp120, and possibly VPR. The combined effects of stress hormones and viral proteins—especially within the thymus and lymph nodes, both viral reservoirs and highly sensitive to immunosuppression—can create a potent barrier to early immune activation. Whether due to external stress, substance use, or direct viral action, this early immunosuppression may prevent the localized inflammatory response needed to eliminate HIV at the point of entry.

Viral Load and Progression to AIDS

Today, viral load in the blood is considered one of the best predictors of disease progression, surpassing CD4+ T cell count as a prognostic marker. Yet most HIV particles in circulation are non-infectious. In a study of 65 infected individuals, only one in 60,000 viral particles, on average, were capable of infection. This raises an important question: how does viral load correlate with disease progression when so few virions are infectious?

VPR and Systemic Immunosuppression

One answer lies in the high concentration of VPR within each viral particle—hundreds, potentially up to a thousand copies. These VPR proteins may increase cellular sensitivity to glucocorticoids even without elevated hormone levels. Consequently, viral particles—infectious or not—might independently trigger systemic immunosuppression, facilitating ongoing viral replication and accelerating the progression to AIDS.