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HIV Infection and AIDS
Infection with the Human Immunodeficiency Virus type 1 (HIV-1) and the resulting condition Acquired Immunodeficiency Syndrome (AIDS) is one of the most devastating diseases in the world. Today, 37 million people globally live with HIV, a prevalence of 0.8% of the world population. More than 34 million lives have been lost since the discovery of the virus in 1981.
HIV weakens the immune system of an infected individual by attacking and killing a type of immune cell called CD4 T cell, which is required to coordinate normal immune responses. If left untreated, HIV infection reduces the number of these immune cells so significantly over time that the infected individual eventually develops AIDS, a condition of severe immunodeficiency characterized by the occurrence of cancers and opportunistic infections.
Despite more than 30 years of research, we still have no cure for HIV infection. However, a new generation of drugs and treatments can enable people living with HIV today to have longer and healthier lives. The administration of combination antiretroviral therapy (ART) suppresses viral replication and slows disease progression, but it cannot eradicate HIV from a person’s body because HIV forms viral reservoirs in which the virus can stay dormant and survive undetected by the immune system for long periods of time. If antiretroviral treatment ceases, the virus reemerges from these reservoirs within a few weeks. Therefore additional strategies for prevention and treatment are needed to manage existing HIV infections and to reduce the worldwide number of new infections.
A vaccine is generally made by inducing the human immune system to produce antibodies against individual fragments or “antigens” of an invading pathogen that will then neutralize the pathogen and aide in its destruction by immune cells. Immunization with HIV-neutralizing antibodies would be a promising tool for both prevention and treatment of HIV infection. As a treatment, anti-HIV antibodies could help to suppress active viral replication and decrease the size of the HIV reservoir.
However, developing potent antibodies against HIV is extremely challenging due to the high genetic diversity of the virus and its ability to escape from specific immune responses by mutation. HIV’s high rate of sequence mutation is caused by the error-prone process the virus utilizes to translate its own RNA genome into DNA that can then be integrated into the host cell genome. Even though HIV has conserved regions that are crucial for maintaining its structure and should be vulnerable to antibody attacks, these regions are often very poor at inducing antibody responses in the first place. Moreover, the virus possesses a carbohydrate-covered coat or “envelope” that shields these antigens from antibodies.
Although HIV-1 infection induces a robust antibody response and these antibodies usually neutralize the initial infecting virus, the emergence of neutralization-resistant viral strains rapidly limits the ability of antibodies to control HIV infection. Thus, a unique set of obstacles hampers the development of fully protective antibodies against all emerging forms of HIV.
Broadly Neutralizing Antibodies
The discovery that some HIV-infected individuals produce HIV antibodies that neutralize a wide range of viral variants has boosted HIV vaccine research in recent years. These broadly neutralizing antibodies (bNAbs) are relatively rare and occur due to a broadening antibody response as a consequence of the antigenic diversification of HIV in the chronic phases of HIV infection.
Over the past years, various bNAbs have been isolated from HIV-infected individuals and their structures and potency have been characterized. Several of these antibodies have demonstrated efficacy in animal models, and some have even been shown to reduce viral load and suppress neutralization-sensitive HIV strains in patients that had not received antiretroviral therapy before.
The Lynch lab aims to investigate the impact of broadly neutralizing antibodies on both the virus and infected cells to explore new avenues for the development of potent preventative and therapeutic agents against HIV infection.
Mapping Virus Escape from Broadly Neutralizing Antibodies
The isolation of broadly neutralizing antibodies against HIV-1 has renewed interest in antibody treatment for chronic infection. Viral escape during monoclonal antibody treatment, however, remains a concern. One class of broadly neutralizing antibodies in particular, the VRC01-class, targets the highly conserved CD4 receptor-binding site (CD4bs) that is critical for viral function and can induce antibody escape mutations that negatively impact the ability of HIV-1 to replicate (Lynch et al., J Virol., 2015). Therefore, bNAbs could aid in treatment of chronic HIV infection by inducing unfavorable mutations that impair viral replication and lower viral burden in the instance of escape.
We have recently demonstrated in human trials that VRC01 can induce escape mutations in the virus of chronically infected individuals (Lynch et al., Science Transl Med., 2015). As human trials with combinations of multiple bNAbs will be assessed in the future, questions related to virus escape must be answered for the design of optimal monoclonal antibody therapy. We are currently mapping virus escape from bNAbs using in vitro replication assays to assess selection pressure of various bNAb combinations on genetically diverse viruses, including non-clade B viruses.