Canadian researchers point to CMV as a problem for the immune system

CATIE News

Want to receive publications straight to your inbox?

CATIE

The widespread availability of potent anti-HIV combination therapy (commonly called ART or HAART) has led to improved health and prospects of prolonged survival among many HIV-positive people in Canada and other high-income countries. ART works by greatly suppressing production of HIV. This allows the body to begin repairs to the immune system, leading to increased levels of T-cells. However, ART does not completely restore the immune system and the reasons for this are under investigation.

Researchers in Newfoundland and Nova Scotia have been conducting studies of the immune system to try to understand the impact of HIV and other viruses. Their findings suggest that co-infection with a member of the herpes virus family, CMV (cytomegalovirus), may be partially responsible for the incomplete recovery of the immune systems of ART users.

Later in this CATIE News bulletin we explain more about CMV and some emerging research on this virus.

Study details

Researchers recruited HIV-positive participants between December 1995 and Sept 2013 for this study. Participants were screened for CMV co-infection (by the presence of antibodies in their blood) and distributed as follows:

  • HIV positive and co-infected with CMV – 97 men, 29 women
  • HIV positive only – 17 men, 10 women

In general, participants had been HIV positive for at least 10 years and they were between 40 and 53 years old.

Understanding cell counts and ratios

Persistent alterations in the amount and ratio of CD4+ to CD8+ T-cells in the blood suggest abnormalities of the immune system.

Among healthy HIV-negative people, the ratio of CD4+ to CD8+ cells is greater than 1 and in some people it approaches 2 (the upper end of the normal range).

In adults with untreated HIV infection, the ratio of CD4+ to CD8+ cells is usually less than 1. This is caused by relatively low numbers of CD4+ cells and relatively high numbers of CD8+ cells in the blood.

Researchers have found that when HIV-positive people take ART, their CD4/CD8 ratio improves. However, these ratios rarely move to the upper end of normal; that is, they rarely reach 2. For most ART users, this ratio remains below 1. This latter finding suggests ongoing immunologic dysfunction.

Residual immunologic problems in some ART users

Some researchers theorize that this dysfunction may be caused by low-level production of HIV and/or other germs. Although ART can greatly suppress production of HIV, small amounts of HIV continue to be produced in parts of the body such as lymph nodes and lymphatic tissues. This low-level production of germs may cause persistent inflammation and activation of the immune system, which could degrade the functioning of many of the body’s key organs and systems over the long-term. Researchers are trying to find ways to suppress this residual activation of the immune system and thereby improve the health of HIV-positive ART users.

Results

The Canadian researchers found that, as a group, people who had HIV but not CMV had greater average CD4+ counts, as follows:

  • HIV positive only – 576 cells/mm3
  • HIV positive and CMV positive – 509 cells/mm3

The researchers also found that CMV co-infected participants had greater average CD8+ counts, as follows:

  • HIV positive only – 702 cells/mm3
  • HIV positive and CMV positive – 881 cells/mm3

The proportions of participants with a CD4/CD8 ratio greater than 1 were distributed as follows:

  • HIV positive only – 55%
  • HIV positive and CMV positive – 13%

All of these differences in cell counts and ratios were statistically significant; that is, not likely due to chance alone.

Results—Aging cells

CD8+ cells are the body’s premier infection-fighting cells. In the present study, Canadian researchers have found that participants whose HIV viral load was lower than 50 copies/ml in the past year and who were CMV-positive had CD8+ cells that were more likely to have proteins on their surface (such as CD28 or CD57), indicating that they were worn out and approaching the end of their lifespan. This suggests that CMV co-infection may be accelerating the aging of the immune system.

CMV and its impact on the immune system

In the present study, researchers assessed CMV infection by the presence of antibodies and did not assess the amount of CMV in the blood (viral load). They chose this route because since the study participants were on ART and had elevated CD4+ counts the amount of CMV in their blood would have been relatively low. CMV can still cause immunologic problems even though the amount of virus in the blood may be low because it can cause complex and unfavourable changes to the immune system and the balance of its different sets of cells.

About CMV

Cytomegalovirus is relatively common among adults. Studies have found that between 50% and 90% of adults have this virus. Rates are likely higher among HIV-positive men who have sex with men (MSM). Generally, CMV is spread by contact with another person’s bodily fluids. Initial infection is usually symptom free. The virus then becomes latent in the average healthy person.

However, among people with weakened immune systems—such as those with transplanted organs/tissue or who have untreated HIV—CMV can become reactivated, causing severe and life-threatening complications. In the time before ART was available, CMV was the cause of a sight-threatening complication called CMV-retinitis, particularly in people who had less than 50 CD4+ cells/mm3. This complication is very rare in high-income countries today.

CMV—Past, present and future

In the early days of the HIV epidemic, some researchers theorized that CMV co-infection was partially responsible for some of the complex immunologic abnormalities detected with blood tests and for speeding up the decline of the immune system and the development of AIDS. CMV may have caused some of these problems because of its ability to incite inflammation and its harmful effects on the immune system.

Emerging research suggests that CMV may be responsible for the accelerated aging of the immune system in both HIV-negative and HIV-positive people. In the present Canadian study, researchers found that participants who had a low HIV viral load (less than 50 copies/ml) and who were co-infected with CMV had abnormalities in their CD4/CD8 ratio and CD8+ cells that seemed prematurely aged. It is possible that CMV co-infection played a role in this accelerated aging of the immune system.

CMV may likely impact other organ-systems. At least one observational study in elderly HIV-negative people suggests that CMV co-infection is associated with an increased risk for dementia. Emerging research suggests that CMV may play a role in accelerating the pace of cardiovascular disease. One study from Italy found that CMV co-infection is linked to an increased risk for heart attack and stroke among HIV-positive people.

Taken together, all of these findings underscore the need for future research on CMV and ways of reducing its potential impact on health.

Our next CATIE News bulletin features emerging research on the impact of CMV on the cardiovascular health of HIV-positive people.

—Sean R. Hosein

REFERENCES:

  1. Barrett L, Stapleton SN, Fudge NJ and Grant M. Immune resilience in HIV-infected individuals seronegative for cytomegalovirus. AIDS 2014; in press.
  2. Fletcher CV, Staskus K, Wietgrefe SW, et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proceedings of the National Academy of Sciences USA. 2014 Feb 11;111(6):2307-12.
  3. Webster A, Lee CA, Cook DG, et al. Cytomegalovirus infection and progression towards AIDS in haemophiliacs with human immunodeficiency virus infection. Lancet. 1989 Jul 8;2(8654):63-6.
  4. Sabin CA, Phillips AN, Lee CA, et al. The effect of CMV infection on progression of human immunodeficiency virus disease in a cohort of haemophilic men followed for up to 13 years from seroconversion. Epidemiology and Infection. 1995 Apr;114(2):361-72.
  5. Barrett L, Walmsley S. CMV retinopathy in the antiretroviral therapy era: prevention, diagnosis, and management. Current Infectious Diseases Reports. 2012 Aug;14(4):435-44.
  6. Lee SA, Sinclair E, Jain V, et al. Low proportions of CD28- CD8+ T cells expressing CD57 can be reversed by early ART initiation and predict mortality in treated HIV infection. Journal of Infectious Diseases. 2014 Aug 1;210(3):374-82.
  7. Fülöp T, Larbi A, Pawelec G. Human T cell aging and the impact of persistent viral infections. Frontiers in Immunology. 2013 Sep 13;4:271.
  8. Welzl K, Weinberger B, Kronbichler A, et al. How immunosuppressive therapy affects T cells from kidney transplanted patients of different age: the role of latent cytomegalovirus infection. Clinical and Experimental Immunology. 2014 Apr;176(1):112-9.
  9. Savva GM, Pachnio A, Kaul B, et al. Cytomegalovirus infection is associated with increased mortality in the older population. Aging Cell. 2013 Jun;12(3):381-7.
  10. Terrazzini N, Bajwa M, Vita S, et al.  A novel cytomegalovirus-induced regulatory-type T-cell subset increases in size during older life and links virus-specific immunity to vascular pathology. Journal of Infectious Diseases. 2014 May 1;209(9):1382-92.
  11. Barnes LL, Capuano AW, Aiello AE, et al. Cytomegalovirus infection and risk of Alzheimer’s disease in older blacks and whites. Journal of Infectious Diseases. 2014; in press.
  12. Lichtner M, Cicconi P, Vita S, et al. CMV co-infection is associated with increased risk of severe non-AIDS events in a large cohort of HIV-infected patients. Journal of Infectious Diseases. 2014; in press.
  13. Emery VC. Re-stimulating interest in cytomegalovirus as a cofactor for HIV infection. Journal of Infectious Diseases. 2014; in press.