| Highly active antiretroviral therapy (HAART) targeted against reverse transcriptase and protease does not eradicate HIV-1 infection. Therefore, it is critical to understand the mechanism responsible for the persistent HIV-1 infection under HAART. The persistent HIV-1 infection has been documented by the presence of replication-competent virus in latently infected resting CD4+ T lymphocytes. However, the mechanism of HIV-1 latency is unknown. In addition, recent studies have shown that virus production continues at a very low level in patients with suppressed levels of plasma virus. It is not clear how this low level of virus release is related to current antiretroviral therapy.; First, we measured HIV-1 DNA and mRNAs in resting CD4+ T lymphocytes from patients on HAART. HIV-1 RNA levels were lower than one RNA molecule per HIV-1 DNA positive resting T cell. Our findings indicate that HIV-1 latency is most likely at the level of transcription. In addition, only 1% of the HIV-1 DNA positive lymphocytes in this compartment could be induced to produce HIV-1 mRNAs following cellular activation, indicating that most of the proviral DNA in resting CD4+ T cells either carries intrinsic defects precluding transcription or is subjected to a profound degree of transcriptional silencing.; Secondly, drug resistant profiles of virus released into plasma of patients with viral loads of less than 50 viral RNA copies/ml receiving HAART were studied. Based on the samples that could be amplified, low-level viremia in children and adults receiving HAART with prolonged suppression of viremia may result primarily from archival, pre-HAART virus, reflecting earlier treatment conditions, and does not appear to require development of new, HAART selected mutations reflecting partial resistance to therapy. The same patterns of drug resistance are found in replication-competent virus of latently infected resting CD4+ T lymphocytes.; Thus, our findings indicate that the reservoir comprised of latently infected resting CD4+ T lymphocytes may be sufficient for the persistence of HIV-1 in patients on HAART. Understanding the mechanisms, such as an epigenetic repression, those render most of HIV-1 DNA in resting CD4 + T lymphocytes incompetent for transcription may facilitate efforts to completely silence this reservoir. |
