HHV6 and HIV

Wisconsin Viral Research Group, Ltd.

Physician's Corner: HHV-6 and HIV

HHV-6 in AIDS

The epidemic of the acquired immunodeficiency syndrome (AIDS) is in its second decade and continues its worldwide expansion. In some developing countries, more than 20% of all adults are infected with the human immunodeficiency virus (HIV).¹ The successful use of multiple antiviral drug therapies has been limited by the complex dosing schedules required and by the emergence of resistant forms of HIV. Work on vaccines to prevent or treat HIV infections continues, but it appears that an effective vaccine is still several years away. Clearly, there exists a need for new strategies in the treatment of HIV disease, especially if these strategies can provide new targets for effective pharmaceutical or immunological therapies. Human herpesvirus six (HHV-6) may serve as an important cofactor in the pathogenesis of AIDS and may provide an alternative target for therapeutic intervention.

Destruction of lymphoid tissues is the root cause of the severe immunodeficiency that characterizes AIDS. The reasons for this tissue destruction remain unclear. Because high levels of HIV are present in lymphoid tissues for years before damage begins, HIV is unlikely to be the direct cause.² In addition, many of the dying cells in the lymphoid tissues of HIV infected patients are not infected with HIV.³ Thus, the event that first triggers the progressive destruction of HIV infected lymphoid tissues remains to be defined.

Work by Wisconsin Viral Research Group (WVRG) has shown that HHV-6 reactivates to active infection early in the course of an HIV infection (absolute CD4 counts > 500/mm3). Early on, these lymph node infections are predominantly due to the A variant of HHV-6 (HHV-6A). Furthermore, cell culture studies by WVRG have demonstrated infection with HHV-6A dramatically enhances the replication of HIV.⁴

Studies have explored the relationship between HHV-6A infection of HIV-infected individuals and the pathological changes present in the tissues. Lymph node biopsies from patients with progressive HIV disease were analyzed for evidence of active HHV-6A infection. All of the lymph node biopsies examined contained cells actively infected with HHV-6A.

Click picture to enlarge.

Lymph node from an HIV-infected patient after staining for active HHV-6A. The infected cells are stained bright red. At the time of lymph node biopsy, the HIV-infected patient had a CD4+ lymphocyte count of over 300 per mm³ and did not have AIDS.

Interestingly, when the results from all of the biopsies were compiled, the densities of HHV-6A infections were significantly (p<0.016) higher in lymph node areas undergoing active destruction than in areas free of destructive changes or in areas in which the lymphoid tissue had been replaced by scar tissue.⁵ Work by WVRG also has shown that, in tissues taken at autopsy, all the patients with AIDS had active HHV-6 infections in essentially every tissue.

These observations strongly support Wisconsin Viral Research Groups’ hypothesis that active HHV-6A infection underlies the lymphoid tissue destruction that occurs in patients infected with HIV, probably through a synergistic interaction between HHV-6A infection and HIV.

In this context, it should be noted that other investigators have presented data concerning the possibility of HHV-6 as a cofactor in the pathogenesis of AIDS. Numerous studies of the HHV-6 serological status of HIV infected individuals have resulted in contradictory conclusions. Such data is difficult to interpret because of the poor diagnostic and prognostic value of herpesvirus serology in immunocompromised patients. Corbellino et al.⁶ demonstrated that HHV-6 DNA is widely disseminated in the tissues of patients with AIDS at the time of their death, and Clark et al.⁷ found that patients with AIDS have significantly elevated levels of HHV-6 DNA in their tissues compared to normal control individuals. Similarly, Dolcetti et al.⁸ detected HHV-6 DNA in 65% of lymph nodes from HIV-infected patients, compared with 20% of lymph nodes from HIV seronegative individuals. HHV-6 positivity strongly correlated with AIDS specific pathological changes. In a longitudinal study of HIV-infected patients, Iuliano et al.⁹ demonstrated reactivation of HHV-6A infection in the patients and correlated this with a dramatic decline in the patients’ CD4+ lymphocyte counts. Emery et al.¹⁰ showed that the presence of HHV-6 in a tissue of an HIV-infected individual closely correlated with an elevated level of HIV in the tissue, consistent with previous observations by WVRG investigators. Finally, studies by Kositanont et al.¹¹ have demonstrated an important role for HHV-6 in the development of AIDS in infants congenitally infected with HIV.

The results from numerous laboratories have consistently indicated HHV-6, and especially HHV-6A, as an important cofactor with HIV in the development of AIDS.

References

1.     Mann JM and Tarantola DJ. HIV 1998: the global picture. Sci Amer 1998; 279:82-83.

2.     Pantaleo G et al. Evolutionary pattern of human immunodeficiency virus (HIV) replication and distribution in lymph nodes following primary infection: implications for antiviral therapy. Nat Med 1998; 4:341-345.

3.     Carbonari M et al. Death of bystander cells by a novel pathway involving early mitochondrial damage in human immunodeficiency virus related lymphadenopathy. Blood 1997; 90:209-216.

4.     Knox KK and Carrigan DR. Active HHV-6 infection in the lymph nodes of HIV infected patients: In vitro evidence that HHV-6 can break HIV latency. J Acquired Immune Defic Syndromes and Human Retrovirol 1996; 11:370-378.

5.     Knox KK and Carrigan DR. Active infection by variant A of human herpesvirus six causes destruction of lymphoid tissues of HIV infected individuals. Manuscript submitted for publication.

6.     Corbellino M et al. Disseminated human herpesvirus 6 infection in AIDS. Lancet 1993; 342:1242.

7.     Clark DA et al. Quantification of human herpesvirus 6 in immunocompetent persons and post-mortem tissues from AIDS patients by PCR. J Gen Virol 1996; 77:2271-2275.

8.     Dolcetti R et al. Human herpesvirus 6 in immunodeficiency virus infected individuals: association with early histologic phases of lymphadenopathy syndrome but not with malignant lymphoproliferative disorders. J Med Virol 1996; 48:344-353.

9.     Iuliano R et al. Human herpesvirus-6 reactivation in a longitudinal study of two HIV-1 infected patients. J Med Virol 1997; 51:259-264.

10.     Emery VC et al. Interactions between B-herpesviruses and human immunodeficiency virus in vivo: Evidence for increased human immunodeficiency viral load in the presence of human herpesvirus six. J Med Virol 1999; 57:278-282.

11.     Kositanont U et al. Primary infection of human herpesvirus 6 in children with vertical infection of human immunodeficiency virus type 1. J Infect Dis. 1999; 180:50-55.