Impaired response to HAART found in HIV-positive individuals with high autonomic nervous system activity

10 January 2002. Related: Antiretrovirals.

Paul Blanchard, HIV i-Base

Norepinephrine is a neurotransmitter secreted by neurons from the sympathetic division of the autonomic nervous system (ANS). These neurons terminate in the parenchyma of all primary and secondary lymphoid organs and release micromolar amounts of norepinephrine into T-cell rich compartments.

In vitro norepinephrine and other cAMP/PKA have been found to enhance HIV-1 replication and in vivo increases in plasma viral load have been observed after pharmacologic enhancement of cAMP activity in circulating lymphocytes. However, the role of neurotransmitters in regulating HIV-replication in vivo has yet to be elucidated.

Antiretroviral therapy can suppress HIV plasma viral load, but infection is not eradicated and residual viral replication maintains an inducible reservoir of infected cells capable of both reigniting viraemia and of allowing the evolution of drug resistant variants. A theoretical concern exists that neural activity modulated by norepinephrine may have an effect on HIV replication in lymphoid tissue and might undermine efforts to minimize viral replication. To the extent that neural activity promotes HIV replication, such nervous system activity may represent a novel physiologic target for therapies supporting antiretroviral drugs.

Steve Cole and colleagues from the University of California chose to examine the role of ANS activity in both the immunologic and virologic response to HAART in a cohort of HIV-infected male patients. They also looked further at the role of norepinephrine in regulating expression of viral coreceptors and HIV-1 gene expression in vitro.

Multiple physiologic indicators of ANS activity were measured before the initiation of HAART in a total of 21 patients and were found to differ significantly across individuals. High ANS activity individuals showed approximately twice the absolute level of activity on each physiologic indicator as those with low ANS activity. However, individual differences in ANS activity were stable over repeated measures.

HAART consisting of one or more protease inhibitors (PIs) and two or more nucleoside analogues (NAs) was initiated and both viral load and CD4+ T cell levels reassessed after an average of 6.3 months. Eight patients discontinued therapy or were non-adherent and were excluded from analysis. When looked at as a separate group, however, these excluded patients showed comparable results suggesting that variable treatment compliance could not explain the observed findings.

ANS activity and virologic response

The researchers found that post-HAART steady state plasma viral load was significantly elevated in individuals showing constitutively high (greater than median) levels of ANS activity before treatment (p=0.017). For individuals with below-median ANS activity, plasma viral load decreased from a median of 16,561 copies/mL to <400 copies/mL after HAART. In contrast, among those showing above-median ANS activity, viral load declined from a pretreatment median of 74,675 copies/mL to 44,776 copies/mL after HAART. In terms of log10 this translates to a 1.61 log10 drop for low ANS activity individuals compared to a 0.86 log10 drop for those showing high ANS activity. In all 71% of low ANS activity individuals achieved posttreatment plasma viral loads <400 copies/mL compared to only 17% of those with high ANS activity. These group differences in post-HAART viral load remained statistically significant in multiple regression analyses controlling for variance in baseline viral load, duration of follow-up, and previous antiretroviral therapy.

ANS activity and CD4+ T cell recovery

As is commonly found during HAART, changes in viral load were strongly predictive of the magnitude of CD4+ T cell recovery. In this study CD4+ T cell recovery was significantly reduced in individuals showing elevated ANS activity. Median CD4+ T cell levels increased by 155 cells/mm3 in those showing low level ANS activity compared to an increase of only 16 cells/mm3 in those with high level ANS activity (p=0.004). Multiple regression analyses controlling for pre-treatment CD4 count and the duration of HAART continued to show an inverse relation between ANS activity levels and CD4+ T cell recovery.

ANS activity and behavioural mediators

ANS activity might be expected to be influenced by both socio-economic and behavioural factors, which have been shown historically to influence response to HAART. However ANS levels did not differ as a function of socio-economic status, recreational drug use, alcohol consumption, age, ethnicity, anxiety, depression, or high risk sexual activity. Moreover, multiple regression analyses controlling for these treatment related variables continued to show poorer virologic suppression and lower CD4+ T cell recovery among individuals with high level ANS activity. The researchers were confident, therefore, that such differences in demographic, behavioural, or treatment characteristics do not appear to account for the impaired response to HAART among high ANS activity individuals.

Effects of norepinephrine in vitro

Cole and colleagues also reported their investigations into the effects of norepinephrine on HIV-1 replication in vitro. Peripheral blood mononuclear cells (PBMC) from uninfected healthy donors were infected in vitro and exposed to physiological amounts of norepinephrine. Replication of both CCR-5 and CXCR4 – tropic strains of HIV was accelerated in the presence of norepinephrine. It was also found that norepinephrine upregulated the cellular expression of both these HIV-1 coreceptors thereby enhancing cellular vulnerability to infection. HIV-1 viral gene expression was also found to be upregulated by norepinephrine.

HIV disease, stress and supportive interventions

These data document an unexpectedly strong linear relationship between constitutive individual differences in ANS activity and residual viral replication in HIV-infected patients treated with antiretrovirals.

The researchers conclude that the data presented suggest that ANS activity may significantly contribute to the biological processes supporting residual HIV replication under HAART and could thus represent a novel target for viral-suppressive and antiretroviral supportive therapies. The results also suggest one physiological mechanism by which stress can influence HIV disease progression.

Reference:

Cole SW, Naliboff BD, Kemeny ME et al. Impaired response to HAART in HIV-infected individuals with high autonomic nervous system activity. Proc Natl Acad Sci U S A 2001 Oct 23;98(22):12695-700.

Full text at:
http://www.pnas.org/cgi/content/full/98/22/12695