ABSTRACT
Since the discovery of AIDS in 1981, over 36 million individuals have died from the disease. In 2020, 37.7 million individuals, including 19.3 women and 1.7 million children, were estimated to be living with HIV. AIDS is caused by the human immunodeficiency virus (HIV), a retrovirus belonging to the lentivirus group, which infects CD4+ helper T cells via CD4, the viral receptor, and a chemokine co-receptor (usually CCR5 or less commonly CXCR4). Virus replication is initiated and completed in activated cells. After viral integration, a small proportion of cells return to the resting state prior to viral gene expression and become latently infected indefinitely.
HIV is transmitted through 1) unprotected sexual intercourse, vertical transmission; 2) mother to infant; 3) contaminated blood or contaminated blood products.
Upon entry into the body via the vaginal or rectal mucosa, HIV infects CD4+ memory T cells and virus is captured by dendritic cells. Virions and infected cells, especially dendritic cells with their cargo of HIV, pass to the draining lymph node, a rich source of susceptible lymphocytes. HIV infection then spreads throughout the body. In this early stage of primary infection, more than half of the body’s memory T-helper cells are lost.
There are three phases to the infection and the immune response plays a role in all – acute, chronic/clinical latency, and AIDS. When the CD4+ T-cell count falls below 200#cells/mm3, patients present with opportunistic infections and tumors. and are diagnosed with advanced disease. AIDs-defining illnesses include a variety of bacterial, viral, and fungal infections and tumors such as Kaposi sarcoma and B-cell lymphomas.
The key pathogenic event leading to immunodeficiency is the death of CD4+ T cells. The mechanisms for this include direct apoptosis mediated by virus infection and via CD8+ T cytotoxic cells killing HIV infected CD4+ T cells.
CD4+ T-cell depletion and dysregulation occur mostly at mucosal sites, especially in the gastrointestinal (GI) tract. T-helper 17 (Th-17) cells mediate immunity against pathogens at mucosal surfaces; their loss from the gut increases intestinal permeability and translocation of microbial products from the gut lumen with consequent hyper-immune activation and irreversible damage to the mucosal barrier.
A combination of three or more active drugs is needed to effectively treat patients with HIV. For example, two or more NRTIs together with an NNRTI or protease inhibitor. This highly active antiretroviral therapy (HAART) is designed to suppress viral replication to undetectable levels, <50#copies/ml, and prevent the emergence of drug-resistant HIV.
Antiretroviral therapy has led to a dramatic improvement of the quality of life of persons living with HIV such that their life span is only reduced by a decade compared with that of the general population. In 2005, globally less than 10% of people living with HIV were able to access treatment. Encouragingly, in 2020, about 70% were in this position after a remarkable WHO-led effort to overcome financial and logistical barriers.
HAART can control virus replication but cannot remove the long-lived reservoir of latently infected cells. If the virus load remained undetectable on therapy stopping infection of new cells, eventually elimination of HIV would be achieved. The problem is that the time estimated to achieve this would be more than 60 years.
The biggest problem in producing HIV vaccines is continuous antigenic drift due to point mutations and high mutation rates. Recent efforts have focused on development of vaccines enhancing the early HIV-specific CD8+ T-cell response to reduce the initial burst of viremia and the frequency of latently infected cells, aimed at increasing the time to progression and reducing transmission of the virus.
Cure from HIV has been reported in just two patients, who underwent an allogeneic bone marrow transplant from a donor homozygous for a lack of CCR5, an essential co-receptor for HIV. Both patients had the transplant to treat another disease, such as leukemia. Based on this, CCR5 has been identified as a good target for a gene editing to protect cells from infection. There is a long way to go before this technology can be transferred from bench to bedside.
