HIV This Week

Farquhar C, Vancott T, Bosire R, Bermudez C, Mbori-Ngacha D, Lohman-Payne B, Nduati R, Otieno P, John-Stewart G. Salivary human immunodeficiency virus (HIV)-1-specific immunoglobulin A in HIV-1-exposed infants in Kenya. Clin Exp Immunol. 2008 ;153(1):37-43.

Humoral immunity, and specifically immunoglobulin A (IgA) that is directed against human immunodeficiency virus (HIV)-1, may contribute to protection against HIV-1 acquisition at mucosal surfaces. HIV-1-specific IgA has been detected in genital tract secretions of HIV-1-uninfected commercial sex workers with HIV-1 exposure, and may be produced in parotid saliva by infants exposed orally to HIV-1 during delivery and breastfeeding. To explore this hypothesis, Farquhar and colleagues collected saliva from 145 infants aged </= 6 months enrolled in a perinatal HIV-1 transmission study in Nairobi and from 55 control infants without HIV-1 exposure who were born to HIV-1-seronegative mothers. Among the 145 infants, 115 (79%) remained uninfected during the 12-month study period and 30 (21%) became HIV-1-infected during follow-up. Nine (8%) of the 115 HIV-1-exposed, uninfected infants had detectable levels of HIV-1 gp160-specific IgA compared with four (13%) of 30 infected infants and none of 55 control infants (P = 0.47 and P = 0.03 respectively). Among the nine HIV-1-exposed, uninfected infants with positive assays, median age was 1 month and none acquired HIV-1 during follow-up. The authors conclude that HIV-1-specific salivary IgA responses may be generated by very young infants exposed perinatally to maternal HIV-1. Mucosal responses would be an appropriate target for paediatric vaccines against breast milk HIV-1 transmission.

Editors’ note: Waning HIV-specific immunoglobulin G (IgG) in an infant’s saliva represents passive transfer of maternal antibodies, whereas detection of HIV-specific IgA indicates infant response to HIV exposure. Although no association was seen with a reduced risk of acquiring HIV, the results of this study provide some evidence that natural HIV exposure via the oral route during delivery and breastfeeding can stimulate a humoral immune response (salivary HIV specific IgA) in infants younger than 6 months of age.

During uncontrolled HIV disease, both tumour-necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and TRAIL receptor expression are increased . Enhanced TRAIL sensitivity is due to TRAIL receptor up-regulation induced by gp120. As a result of successful antiretroviral therapy TRAIL is down-regulated, and there are fewer TRAIL-sensitive cells. In this setting, Shepard and colleagues hypothesized that all cells that contain virus, including those productively- and latently-infected, have necessarily been "primed" by gp120 and remain TRAIL-sensitive, whereas uninfected cells remain relatively TRAIL-resistant. The authors evaluated the immunologic and antiviral effects of TRAIL in peripheral blood lymphocytes collected from HIV-infected patients with suppressed viral replication. The peripheral blood lymphocytes were treated with recombinant TRAIL or an equivalent amount of bovine serum albumin as a negative control. Treated cells were then analyzed by quantitative flow cytometry, ELISPOT for CD4+ and CD8+ T-cell function, and limiting dilution microculture for viral burden. Alterations in the cytokine milieu of treated cells were assessed with a multiplex cytokine assay. Treatment with recombinant TRAIL in vitro reduced viral burden in lymphocytes collected from HIV-infected patients with suppressed viral load. TRAIL treatment did not alter the cytokine milieu of treated cells. Moreover, treatment with recombinant TRAIL had no adverse effect on either the quantity or function of immune cells from HIV-infected patients with suppressed viral replication. In conclusion, TRAIL treatment may be an important adjunct to antiretroviral therapy, even in patients with suppressed viral replication, perhaps by inducing apoptosis in cells with latent HIV reservoirs. The absence of adverse effect on the quantity or function of immune cells from HIV-infected patients suggests that there is not a significant level of "bystander death" in uninfected cells.

Editors’ note: The mechanism by which activation of TRAIL signalling induces reductions in viral load is unclear and this work is ‘in vitro’ (meaning in the laboratory, as opposed to ‘in vivo’ meaning in humans). TRAIL signalling might induce the death of infected cells without killing other cells or reduce viral load in some other way without causing adverse effects. There are very preliminary but nonetheless intriguing results.

For most viruses, there is a need for antimicrobials that target unique viral molecular properties. Acyclovir is one such drug. It is activated into a human herpesvirus DNA polymerase inhibitor exclusively by human herpesvirus kinases and, thus, does not suppress other viruses. Here, Lisco and colleagues show that acyclovir suppresses HIV-1 in herpesvirus -coinfected human tissues, but not in HHV-free tissue or cell cultures. However, addition of HHV-6-infected cells renders these cultures sensitive to anti-HIV acyclovir activity. The authors hypothesized that such HIV suppression requires acyclovir phosphorylation by human herpesvirus kinases. Indeed, an acyclovir monophosphorylated prodrug bypasses the human herpesvirus requirement for HIV suppression. Furthermore, phosphorylated acyclovir directly inhibits HIV-1 reverse transcriptase, terminating DNA chain elongation, and can trap reverse transcriptase at the termination site. These data suggest that acyclovir anti-HIV-1 activity may contribute to the response of HIV/human herpesvirus-coinfected patients to acyclovir treatment and could guide strategies for the development of new HIV-1 reverse transcriptase inhibitors.

Editors’ note: This study suggests that acyclovir, commonly used to treat herpes simplex, could potentially have a direct effect on HIV beyond the indirect effects that suppression of another infection can have on HIV. This direct effect appears to rely on the presence of a human herpes virus, such as the ubiquitous human herpes virus-6, to provide enzymes that phosphorylate acyclovir in infected cells. After further conversion into its antiviral active form, acyclovir then fights herpes but it might also fight HIV, because this active form happens to be a reverse transcriptase inhibitor. Clinical trials are needed to determine whether there is a potential role in combination HIV treatment of low toxicity, low cost acyclovir, a drug that has been used for over 30 years.