Morphine effects on HTLV-I infection in the presence or absence of concurrent HIV-1 infection.

Human T-cell leukemia virus type I (HTLV-I) infection is emerging as an important complication in HIV infection and AIDS in injecting drug users. HIV-1 and HTLV-I share a common host in CD4+ T lymphocytes. However, the result of HIV-1 infection is the decimation of this cell population, whereas a hallmark of HTLV-I infection is the inappropriate proliferation of infected cells. Combined epidemiologic data suggest that HTLV-I infection is enhanced during concurrent HIV-1/HTLV-I infection; however, there are currently no in vitro studies focusing on the effects of drugs of abuse on retrovirus coinfection. We have found that in an in vitro coinfection system (HIV-1 + HTLV-I), morphine treatment further enhanced the levels of HTLV-I p19. In addition, indicators of in vitro infection by cell-free HIV-1 were reduced by morphine treatment in both single and dual in vitro infection experiments. Interleukin 2 levels in the affected cultures were found to increase with combined HTLV-I infection and morphine treatment. These in vitro results indicate the need to further explore the activity of HTLV-I within opiate-treated cells, as this oncoretrovirus appears to be especially sensitive to morphine-induced alterations to its host cell environment.

DNA vaccination with HIV-1 expressing constructs elicits immune responses in humans.

Humoral and cellular immune responses have been produced by intramuscular vaccination with DNA plasmids expressing HIV-1 genes, suggesting possible immunotherapeutic and prophylactic value for these constructs. Vaccination with these constructs has decreased HIV-1 viral load in HIV-1-infected chimpanzees. In addition, naive (i.e. non-HIV-1-infected) chimpanzees were protected against a heterologous challenge with HIV-1. Ongoing phase I clinical trials show that therapeutic vaccinations indeed boost anti-HIV-1 immune responses in humans. A therapeutic phase I trial on humans with these constructs induced a good safety profile and also demonstrated an immunological potentiation. These findings indicate that further studies with these constructs in humans are warranted.

Opiate effects on in vitro human retroviral infection.

The transmission and progression of the human retroviruses HIV-1 and HTLV-1/2 can be most likely influenced by a variety of "lifestyle cofactors" which includes the use of certain injected pharmaceuticals. Some investigations have suggested that HIV-1 infected individuals who are injecting drug users (IDUs) may undergo an accelerated rate of progression to AIDS. It is known that opioid receptors exist on cells pertinent to immune function, and that the activation or inhibition of these receptors may enhance or down-regulate some cell activities. The mechanisms for these effects have not yet been elucidated, nor have the effects of opioids on retroviral infection models been fully determined. While some work has been performed on the effects of opiates on infection by HIV-1 and SIV virtually no work has been done on the potential effects of this class of drugs on HTLV-1 and 2 infection. The potential effects of opiates on these retroviruses are important because of the higher incidence of infection in IDUs. Because IDUs compose one of the emerging high risk populations for infection with HIV-1 and more recently HTLV it is relevant to analyze the direct and indirect effects of opioids on the progression of retroviral infections. Our preliminary results from in vitro syncytia formation studies suggest a modulation by opioid-selective receptor agonists of in vitro infection by both HIV-1 and HTLV-I. These initial results underscore the necessity for further studies to define and elucidate the role of opiate abuse in the infection by human retroviruses as well as the associated pathogenesis.

Cannabinoid receptor agonists enhance syncytia formation in MT-2 cells infected with cell free HIV-1MN.

Marijuana and other drugs have been suggested to act as cofactors for HIV infection. Interestingly, delta 9-THC has been shown to upregulate NF kappa B, a transcription factor utilized by HIV. Therefore, it was of interest to investigate whether cannabinoids can modulate HIV infection and replication. Initially, we tested for evidence of receptor expression by examining for receptor mRNA in various cell lines used to study HIV infection and replication. Cellular RNA was isolated from SupT, and H9, H9MN, and MT-2 cells and RT-PCR was performed. Results showed that, although all of the cell lines tested were positive for CB2 mRNA, only the MT-2 cells also expressed CBI mRNA. Since the MT-2 cells expressed both CBI and CB2 receptor mRNA, we next wanted to determine whether different cannabinoid receptor agonists such as CP-55,940, delta 9-THC, WIN-55,212-2, and WIN-55,212-3 influenced infection of these cells by cell free HIV-1MN. Infectivity assays were performed where MT-2 cells were incubated with drug and cell free virus for 90 min, the free virus washed off, and the cells incubated further, and checked for virus growth by syncytia formation. It was found that the drugs significantly increased syncytia formation when MT-2 cells were cultured in the presence of both drug and cell free HIV-1MN. In conclusion, of the cell lines tested, only the MT-2 cells were positive for both CB1 and CB2 mRNA. In addition, since syncytia formation is an indication of virus infection and cytopathicity it was concluded that cannabimimetic drugs may enhance HIV-1 infection of susceptible cells.