Background of the Science

Natural Resistance to HIV Infection

Studies show that some individuals at high risk for HIV infection remain uninfected. In some cases, genetic mutations are responsible. These mutations affect membrane receptors that generally bind HIV, preventing the virus from entering susceptible cells. However, in other cases, the cause of resistance is unclear. While some individuals naturally fend off HIV, others cannot.

If the natural resistance mechanism were clearly understood, vaccine development could mimic this strategy. One hypothesis is that the immune system fails to control HIV because the virus can stimulate its own expression while suppressing the immune response to its presence.

Explaining the Decline in CD4 T Cells

For years, scientists struggled to explain why CD4 T cell counts dropped in AIDS patients. Few of the T cells in peripheral blood were found to contain the virus. This led to speculation that HIV might not be the cause of AIDS. Additionally, the asymptomatic stage of AIDS can last for a decade or more. Many believed the immune system held the virus in check during this time.

This belief has changed. Research now shows the immune response is unable to fully suppress the virus. HIV contains components that interfere with immune recognition. After infection, a sharp drop in viral levels likely results from apoptosis of infected cells. This is triggered by the HIV protein VPR and immune complexes targeting gp120. However, viruses with mutations in VPR avoid apoptosis. They continue replicating, though at a reduced rate.

Revisiting Protease Inhibitor Findings

In 1995, two Nature studies reported that HIV protease inhibitors significantly reduced HIV RNA in the blood. They also increased CD4 T cell counts. This was surprising. Scientists expected infected cells to keep producing non-infectious viruses, even under treatment. The expectation was that viral RNA would remain in the blood.

The studies concluded that HIV spread depends on the infection of new cells. They proposed that viral particles and infected cells had short life spans. They believed that protease inhibitors blocked new infections. Infected cells then died and were replaced by new CD4 cells. However, this interpretation is no longer considered accurate.

CD4 T Cell Turnover in Infected Individuals

There is little evidence to support the rapid production and destruction of CD4 T cells during HIV infection. When researchers compared telomere lengths in CD4 T cells from infected and uninfected individuals, they found no difference. Since telomeres shorten with each cell division, this suggests normal turnover.

Additional analysis of lymph nodes in HIV-positive individuals found far less cell turnover than predicted by the 1995 studies. The decline in CD4 T cells could be due to several factors. These include reduced production in the thymus, programmed cell death, or cell migration out of the bloodstream.

Protease inhibitors may reduce HIV RNA by preventing viral proteases from degrading key cytoskeletal proteins, which help regulate viral secretion. When overexpressed, viral proteases can degrade actin, vimentin, myosin, and other structural elements. The HIV protein VIF also binds vimentin, a protein that helps link the cell membrane to the nucleus. Disruption of this network can trigger apoptosis.

The Role of the Cellular Environment

Reverse transcriptase binds to beta-actin. When infected T cells bind fibronectin or other cells, actin filaments reorganize. They form a dense ring under the cell membrane, reducing viral secretion by 40% within 48 hours. This reorganization does not occur when cells are cultured on polystyrene, a common plastic in lab dishes.

Infected cells reside in lymph nodes and thymus tissues, which contain fibronectin and other extracellular matrix proteins. Such cellular contacts may slow or impair viral release. In lab settings, viral proteases may not be needed for virus release. In the body, however, they may help reshape the cytoskeleton to support viral exit. Thus, protease inhibitors may reduce HIV RNA by limiting this function.

Proteasome Inhibition and Immune Activation

Protease inhibitors may also affect the proteasome. They inhibit its chymotrypsin-like activity. This leads to apoptosis in infected cells. The proteasome usually degrades inhibitors of the NF-κB transcription factor. When the proteasome is blocked, these inhibitors accumulate. As a result, genes that depend on NF-κB—such as those for inflammation, cell survival, and HIV replication—are not activated.

Without these signals, infected cells die, and the virus cannot infect new cells. The proteasome is also needed to process HIV gag polyproteins, which are essential for viral maturation. Specific inhibitors like epoxomicin block this processing and reduce viral release. If commercial HIV protease inhibitors were truly specific to the viral protease, these effects would not be observed. Their effectiveness may stem from broader actions on cellular proteasomes.

Key Questions for Vaccine Development

Understanding why CD4 T cells decline is essential for developing a vaccine. Are T cells dying too quickly, or are they not being replaced? Could they be relocating to other tissues?

If neutralizing antibodies against gp160/120 could eliminate HIV at entry, these questions would matter less. Such antibodies block infection, trigger complement activation, and destroy the virus. Unfortunately, HIV’s complexity makes this approach insufficient on its own.

A typical antiviral immune response includes an early inflammatory phase. This is followed by a feedback phase of immunosuppression, which prevents excessive damage. In HIV, these phases may be reversed. During the asymptomatic stage, the immune system fails to launch a strong defense. Meanwhile, various immune and hormonal factors keep the virus in check—until they fail.

Immunosuppressive HIV Proteins

Several HIV proteins—NEF, VPR, TAT, and p24/p17—suppress the immune response and may contribute to viral persistence. Effective vaccines should target these proteins as soon as they are released from viral particles or infected cells. If the virus cannot induce immunosuppression, the immune system may clear it more effectively.

Rethinking the gp160/gp120 Vaccine Target

There is increasing concern about using gp160/120 in vaccine design. Although it plays a role in HIV pathogenesis, targeting it might be harmful. Anti-gp160/120 immune complexes can bind to macrophages and dendritic cells. These complexes may crosslink CD4 on uninfected T and B cells, leading to apoptosis.

Research from the American Red Cross supports this idea. Scientists immunized transgenic mice that expressed human CD4. After gp120 immunization, the mice showed a sevenfold drop in CD4 T cells and a two- to threefold drop in B cells within six days. The findings suggest that these immune complexes sensitize and kill uninfected cells.

Therefore, the safest immune response to gp160/120 may be tolerance—not active targeting.