CD8 T-cells in HIV infection

CD8 T-cells play a crucial role in controlling HIV replication during the early phase of infection. HIV-specific CD8 T-cells are targeted at the dominant viral variant and their emergence is associated with a rapid fall in viral load before the development of an antibody response.

A majority of the CD8 T-cells generated during primary infection die within a few weeks, leaving a reservoir of HIV-specific CD8 memory T-cells that will persist, regardless of the presence of antigen or CD4 helper T-cells. Researchers have found that viral load is better controlled in people whose HIV-specific CD8 T-cells mature fully into 'effector memory' T-cells.1 2 

Several theories have attempted to account for the gradual failure of CD8 T-cells to control HIV replication. The 'viral escape' theory states that the cells begin to lose the ability to recognise HIV's genetic sequences due to the high level of viral turnover and mutation. One study found that CD8 T-cells lose their ability to recognise and kill viral variants, even though they may be responsive to normal 'wild type' viruses.

Researchers compared CD8 cytotoxic T-cells from HIV-infected asymptomatic individuals with those from symptomatic AIDS patients and found that CD8 T-cells from asymptomatic individuals could recognise and kill both types of target cells. In contrast, the CD8 T-cells from symptomatic patients, while still able to recognise and eliminate the laboratory strain targets, no longer killed target cells infected with their own virus. Additionally, HIV-specific CD8 T-cells may fail to produce the cytotoxic molecule, perforin, which CD8 cells use to kill virus-infected cells.3 

Without helper T-cells, which slowly disappear during HIV disease, the CD8 T-cells are unable to keep up with the increasingly diverse population of HIV inside the body. As HIV mutates in the body, due to several factors including pressure from antiretroviral medications, these CD8 T-cells become increasingly irrelevant.

CD8 T-cells have been shown to express CD4 receptors on their surface following activation through the T-cell receptor, permitting infection by HIV. Some suggest this is a mechanism through which CD8 T-cells become depleted late in infection.

A recent study suggests that in chronic HIV-1 infection, the constant presence and pressure of HIV-1 antigen causes the functional impairment of virus-specific CD8 T-cell response. As antiretroviral treatment was able to reverse this impairment by reducing the amount of antigen, it suggests that the amount of antigen is the cause and not the result of CD8 T-cell depletion.4

HIV-specific CD8 T-cells that proliferate and produce IL-2 are associated with HIV-specific CD4 T-cells with the same proliferative and IL-2 secreting characteristics. This is usually only seen in people who can control viral load, such as long-term non-progressors.5 6 Strong CD4 T-helper cell and CD8 T-cell responses correlate with long-term non-progression. A therapeutic vaccine that would restore HIV-specific CD4 T-cell and CD8 T-cell responses is one approach that has been looked at to help immune control of HIV.

High levels of the activation marker human leukocyte antigen (HLA)-DR on CD8 T-cells has been associated with slower disease progression, as has decreased antigen expression of CD38 on CD8 cells.7 8 9 10 Very rarely, an efficient CD8 T-cell response can occur before HIV has started to replicate in CD4 T-cells or macrophages. This can prevent HIV infection before the production of HIV antibodies. This may occur more frequently in newborn babies than in adults.

CD8 antiviral factor and chemokines

CD8 cytotoxic T-cells appear to produce a cytokine called CD8 antiviral factor (CAF) that inhibits HIV replication, and may or may not directly kill CD4 T-cells. While some researchers believe that CAF is composed of the RANTES, MIP-1alpha and MIP-1beta chemokines that are thought to block the CCR5 receptor, when these cytokines are blocked with monoclonal antibodies, another HIV-suppressive factor still appears to be at work.

Despite this, chemokines may still have a role in suppressing HIV, as high levels of beta-chemokines have been associated with delayed HIV disease progression.11

Chemokine activity declines during the course of HIV infection. The only test of an artificial chemokine as a therapy so far failed to demonstrate antiviral efficacy. Researchers are now looking at whether they need to give higher doses or to administer chemokines in a different way.

Chemokine receptor genes may also affect the response to antiretroviral treatment, as people with the genotype CCR5+/+, CCR2+/+, and CCR5-59029 A/A were found in one study to be 2.5 times less likely to sustain undetectable viral load with triple therapy.12


  1. Hess C et al. HIV-1 specific CD8+ T-cells with an effector phenotype and control of viral replication. Lancet 363: 863-866, 2004
  2. van Baarle et al. Failing immune control as a result of impaired CD8+ T-cell maturation: CD27 might provide a clue. Trends Immunol 23 (12): 586-591, 2002
  3. Migueles SA et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 3: 1061-1068, 2002
  4. Steeck H et al. Antigen load and viral sequence diversification determine the functional profile of HIV-1–specific CD8+ T-cells. PLoS Medicine 5 (5), e100 doi/10.1371/journal.pmed.0050100, 2008
  5. Boaz M et al. Presence of HIV-1 gag-specific IFN-gamma+ IL-2+ and CD28+ IL-2+ CD4 T cell responses is associated with non-progression in HIV-1 infection. J Immunol 169: 6376-6385, 2002
  6. Hess C et al. HIV-1 specific CD8+ T-cells with an effector phenotype and control of viral replication. Lancet 362: 863-866, 2004
  7. Shepard BD Early changes in T-cell activation predict antiretroviral success in salvage therapy of HIV infection. J Acquir Immune Defic Syndr 48(2):149-155, 2008
  8. Benito JM et al. Differential upregulation of CD38 on different T-cell subsets may influence the ability to reconstitute CD4+ T cells under successful highly active antiretroviral therapy. J Acquir Immune Defic Syndr 38:373-381, 2005
  9. Beron O et al. CD38 expression on CD8+ T cells in human immunodeficiency virus 1-positive adults treated with HAART. Acta Virol 47:121-124, 2003
  10. Giorgi JV et al. Shorter survival in advanced HIV type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis 179: 859-870, 1999
  11. Garzino-Demo A et al. Spontaneous and antigen-induced production of HIV-inhibitory beta-chemokines are associated with AIDS-free status. Proc Natl Acad Sci U S A 96: 11986-11991, 1999
  12. O'Brien TR et al. Effect of chemokine receptor gene polymorphisms on the response to potent antiretroviral therapy. AIDS 14: 821-826, 2000
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.