A Patient With HIV-1 Superinfection
New England Journal of Medicine, September 5, 2002, (Stephanie Jost, et al.)
- A case report involving one 38 year old male, initially diagnosed with acute HIV infection in November 1998. At that time, anti-HIV antibodies were not yet detectable and the viral load was 805,000 copies. He enrolled in the QUEST trial and was treated with HAART (AZT, 3TC, Ziagen and Agenerase) for 27 months. From month 21-27 he also received immunizations with the experimental HIV vaccine ALVAC vCP1452.
- HAART was interrupted in January 2001, which led to a rebound in viral load that peaked at 80,000 copies and subsequently declined to 21,000 copies. A viral load test on April 10, 2001 revealed an increase to over 200,000 copies (which the researchers describe as the "second rebound") and the viral load remained between 200,000 and 400,000 copies for the next four months.
- Attempts to restart HAART were delayed after the development of liver toxicity, which caused the researchers to look for evidence of hepatitis. It was discovered that the individual had very recently become infected with the hepatitis C virus.
- Detailed analysis of HIV samples revealed that this individual was originally infected with virus of the subtype AE (a combination form of subtype A and subtype E). However, the second viral load rebound was associated with the emergence of a subtype B HIV, most closely related to subtype B viruses circulating in Brazil. (The report notes that the subtype B virus replicated more efficiently in vitro compared to the original AE virus, and this finding was mirrored in vivo by a decline in AE virus levels as the subtype B virus levels increased.)
- Further investigation revealed that, three weeks prior to the second rebound, the individual had visited Brazil and had several unprotected sexual contacts, leading the researchers to conclude that the subtype B HIV represented a superinfection.
- It appears that infection with hepatitis C occurred at around the same time. (Whether the acquisition of hepatitis C influenced susceptibility to HIV infection -- which might theoretically result from hepatitis C-induced activation of the immune system -- is unclear, and the researchers do not discuss the possibility in the report.)
- In terms of immune responses, CD8 T cells directed against a single epitope (a tiny slice of viral protein) from the AE virus were detected using an ELISpot assay (which detects specific CD8 T cells based on their ability to make the cytokine interferon-gamma in response to stimulation with a given epitope in vitro) from November 1998 onwards, but began to decline in March 2001 (as the subtype B virus appeared). Typically, CD8 T-cell responses are directed at multiple epitopes, suggesting a narrowly targeted immune response in this individual prior to superinfection. No responses to any epitopes from the subtype B virus were detected. Data on HIV-specific CD4 T-cell and antibody responses were not reported.
Intersubtype HIV-1 Superinfection Following Seroconversion to Primary Infection in Two Injection Drug Users
Journal of Virology, August 2002, (Artur Ramos et al.)
- Two individual cases identified by analyzing stored samples from a cohort study of injection drug users in Bangkok, Thailand.
- The first case comprised a 30 year old Thai woman who tested HIV negative at the time of enrollment in June 1996. Four months later, the HIV antibody test was positive. Additional samples were collected at around 4 and 7 weeks after the positive antibody test. Follow-up subsequently occurred every four months.
- Virus samples up at the time of the positive antibody test and the first follow-up visit three weeks later all belonged to a subtype known as CRF01-AE (a circulating recombinant form of HIV subtypes A and E).
- From the second follow-up visit onwards, virus samples also contained a proportion of subtype B HIV, leading the researchers to conclude that a superinfection most likely occurred in the interval between first (24 December 1996) and second (17 January 1997) follow-up visit.
- The second case comprised a 32 year old Thai male who initially tested positive in 1996.
- Virus samples from early time points exclusively belonged to HIV subtype B.
- Approximately seven months after seroconversion, viruses belonging to CRF01-AE also became detectable, suggesting that a superinfection with this strain most likely occurred in the interval between the third (19 January 1997) and fourth (25 June 1997) follow-up visit.
- Antibody responses to the V3 envelope peptides of both HIV subtypes were assessed. In case 1, antibodies to the AE strain were present from seroconversion onwards. Antibodies to subtype B were not detected until the fourth follow-up visit. In case 2, the pattern was similar but reverse order: antibodies to subtype B were detectable from seroconversion, while reactivity to the AE strain was not seen until the fourth follow-up visit. This is consistent with the idea that superinfections had occurred within months of the initial infection.
- HIV-specific T cells were evaluated using an ELISpot assay to detect interferon-gamma production in response to whole HIV proteins (env, gag, nef and pol) derived from either subtype B or AE. The assay measures both CD4 and CD8 T-cell responses, and the relative contributions of these subsets were not assessed.
- For case 1, T-cell responses were initially mainly directed against gag and pol from the AE strain, with a minor contribution of T cells specific for subtype B gag. Over the course of follow-up, the number of T cells reactive against the initial infecting strain (AE) declined slightly while those specific for the second infection (subtype B) increased.
- Case 2 showed a low level T-cell response to the initial infecting strain (B) and no response to the super-infecting strain (AE) initially. By the time superinfection was detected, however, there were increased numbers of T cells reactive to the initial infecting strain (B) and new responses to all four (super-infecting) AE proteins. The number of T cells specific for both HIV subtypes subsequently declined.
|Bodies of Evidence|
|Strain 1||Strain 2||Time to 2nd Infection|
|B||B||> 18 months|
|Source: N Engl J Med 2002; 347: 731-36; J Virol 2002; 76(15): 7444-52; XIV International Conference on AIDS, 7/2002.|