HIV Does Not Cause AIDS in the Way We Thought

Research Reveals Why Vaccines Fail to Prevent Infection

Electron micrograph of a HIV-1 virions (in green) budding from an infected CD4+ T-cell. Photo Credit: C. Goldsmith/Centers for Disease Control and Prevention

For decades, it was believed that HIV progressed to AIDS in a pretty straightforward manner: spreading through the body as free-circulating virus, attaching itself to immune cells (predominately CD4+ T-cells) and hijacking their genetic machinery in order to create multiple copies of itself. By doing so, HIV is able to disseminate throughout the entire system, expanding in numbers until enough T-cells are killed to fully compromise a person's immune defenses (the clinical definition of AIDS).

New research suggests that this is probably not the case, or at least not the disease pathway we had long presumed. In fact, since as far back as the late-1990s, scientists had begun to observe that HIV can also spread directly from cell to cell without creating any free-circulating virus.

This secondary mode of transmission, according to research from the San Francisco-based Gladstone Institute of Virology and Immunology, is between 100 and 1,000 times more efficient in depleting CD4 cells than free-circulating virus and may help explain, in part, why current vaccine models are unable to adequately prevent or neutralize HIV.

By transmitting itself from cell to cell, HIV can cause a cellular chain reaction in which the immune cells literally commit suicide in mass volumes.  Research suggests that as much as 95 percnt of CD4 cell death is caused in this manner, as opposed to only 5% with free virus.

Explaining Cell-to-Cell Transmission

Cell-to-cell transfer of HIV occurs through so-called "virological synapses," in which the infected cell adheres to a "resting" host cell and employs viral proteins to breach the cellular membrane. (The process was captured on video in 2012 by scientists at UC Davis and Mount Sinai School of Medicine.)

Once invaded, the host reacts to the fragments of deposited viral DNA, triggering a process called pyroptosis wherein the cell recognizes the danger signals and gradually swells and explodes, killing itself.  When this occurs, the burst cell releases inflammatory proteins called cytokines which signal other immune cells to the attack—cells that are then actively targeted for HIV infection.

The Gladstone researchers were able to show that by preventing cell-to-cell contact—through chemical inhibitors, synaptic blockers, or even physically separating the cells—CD4 cell death was effectively stopped. They concluded that cell-to-cell contact was "absolutely required" in order for cell death (and disease progression) to take place.

Implications of the Research

What makes these findings particularly important is that they not only explain the mechanisms for CD4 cell depletion, they also spotlight inherent weaknesses in current vaccine design.

By and large, HIV vaccine models have focused on priming the immune system to recognize and attack surface proteins on free-circulating virus.

When HIV is transmitted from cell to cell, however, it is essentially impervious to attack, shielded from detection from within the very construct of the infected cell.

In order to overcome this, newer models will need to help the immune system better target proteins vital to synaptic formation and/or to create antiviral agents that can inhibit the synaptic process.  If this can be achieved, the ability of HIV to progress to AIDS could be profoundly limited, or even stopped.

While the mechanisms for cell-to-cell transmission are not yet fully understood, the findings represent a profound change in our understanding of how HIV progresses to AIDS and provides us a glimpse into the possible strategies for HIV eradication.


Carr, J.; Hocking, H.; Li, P.; et al. "Rapid and Efficient Cell-to-Cell Transmission of Human Immunodeficiency Virus Infection from Monocyte-Derived Macrophages to Peripheral Blood Lymphocytes." Virology. December 20, 1999; 265(2): 319-329.

Galloway, N.; Doitsh, G.; Monroe, K.; et al. "Cell-to-Cell Transmission of HIV-1 Is Required to Trigger Pyroptotic Death of Lymphoid-Tissue-Derived CD4 T Cells." Cell Reports. August 4, 2015; published online; DOI:

Doitsh, G.; Galloway, N.; and Geng, X. "Cell Death by Pyroptosis Drives CD4 T-Cell Depletion in HIV-1 Infection." Pediatrics. November 1, 2014; 134(3): 509-514.

University of California Davis Center for Biophotonics Science and Technology. "First-ever video reveals how HIV spreads between immune cells." Sacramento, California; press release issued March 27, 2009.

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