Neutralization of HIV-1: a paradox of humoral proportions.
Abstract: The production of immunoglobulin capable of neutralizing the infectivity of a virus represents one of the most remarkable molecular accomplishments of the host's available immune defenses. It should be no surprise that a virus that has existed in the parenchyma of the immune system has evolved as an equally dynamic molecule (i.e., viral envelope) for survival. Neutralizing immunoglobulin (Ig) can best serve the host under conditions where the invading pathogen requires a well-defined cell-free state for establishing an infection or transmission. Evidence for a controlling and therefore protective role of neutralizing Ig against lentiviruses has been defined in natural and experimental infections with equine infectious anemia virus of ungulate members in the family equidae. Rapid replication of the virus immediately after infection and its release in a cell-free state leads to the production of neutralizing Ig and subsequent control of the primary viremia. A similar cause-effect relationship exists in humans between the high-titered viremia, observed shortly after HIV-1 infection, and the subsequent production of neutralizing Ig. Partially controlling this acute stage of viral replication by neutralizing Ig and thus preventing an otherwise acute form of immunosuppression or immune complex disease may be viewed paradoxically as a survival property of the virus. Immunologically mediated control, in a Darwinian sense, selects for viruses that have optimized the parameters of longevity and transmission from host to host. This paradox of neutralization in HIV-1 infection appears to be mediated by the convergence of structural and functional roles of the third variable domain (V3) of the external envelope glycoprotein. During infection or envelope-based vaccination, antibody to this cross-reactive, immuno-dominant epitope dominates the antigenic repertoire. Once this occurs, the host is less able to respond to emerging viruses containing closely related V3 structures. Thus a relatively restricted clonal-dominance of the neutralization response results. The V3 domain, apparently in concert with the rest of the molecule, provides an epitope that can tolerate and utilize its conformational flexibility to allow immune escape while maintaining its functional role in infectivity. Sixteen other putative epitopes have been described as being involved in the induction of neutralizing Ig. Currently the biologically functional role of neutralizing Ig to these other epitopes are complicated by a prior lack of knowledge and appreciation of the in vitro variables affecting their measurements.(ABSTRACT TRUNCATED AT 400 WORDS)
Publication Date: 1991-07-01 PubMed ID: 1712328DOI: 10.1096/fasebj.5.10.1712328Google Scholar: Lookup
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Summary
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The research focuses on how the human immune system produces specialized antibodies to neutralize HIV-1, a virus that disrupts the immune system. However, the successful neutralization can paradoxically enhance the survival and transmission of the virus, partly due to the adaptability of a particular protein on the virus.
Neutralizing Immunoglobulin
- The body produces a specific type of immunoglobulin (Ig or antibodies) that can neutralize viruses, which is a significant achievement of the immune system against viral infections.
- These neutralizing antibodies are particularly effective against viruses like HIV-1 that require a ‘cell-free’ state to establish an infection.
Protective Role of Neutralizing Immunoglobulin
- Studies on equine infectious anemia virus (a lentivirus like HIV) in horses show that infection leads to rapid virus replication which then prompts the production of neutralizing antibodies, ultimately controlling the initial wave of the infection.
- This pattern is seen in humans as well, where the onset of HIV-1 infection leads to high viral levels, which subsequently prompts the production of neutralizing antibodies.
- The act of controlling this acute stage of infection prevents severe immunosuppression or immune complex disease, which can be viewed paradoxically as aiding the survival of the virus.
The Paradox of Neutralization in HIV-1
- Darwinian natural selection shapes viruses that can cope best with the immune defenses, so neutralization can indirectly facilitate the survival and transmission of the virus.
- This paradox is centered around the V3 domain, a structural feature of the viral envelope protein. It elicits a strong immune response leading to the production of antibodies.
- However, this strong response to the V3 domain limits the immune system’s ability to react to emerging variants of the virus with similar V3 structures.
- The V3 domain can adjust its structure to evade the immune system while maintaining its role in the virus’s ability to infect cells.
- Scientists have identified 16 additional potential targets (epitopes) that could induce the production of neutralizing antibodies. However, understanding their roles is complicated by previous gaps in knowledge and variations in laboratory measurement techniques.
Conclusion
- This research adds to the understanding of the complex interplay between HIV-1 and the host’s immune response. It underscores the adaptability of HIV-1 and its ability to use the immune system’s response to its advantage – a critical consideration for developing effective vaccines and treatments.
Cite This Article
APA
Nara PL, Garrity RR, Goudsmit J.
(1991).
Neutralization of HIV-1: a paradox of humoral proportions.
FASEB J, 5(10), 2437-2455.
https://doi.org/10.1096/fasebj.5.10.1712328 Publication
Researcher Affiliations
- Laboratory of Tumor Cell Biology, National Cancer Institutes-Frederick Cancer Research and Development Center, Maryland 21702-1201.
MeSH Terms
- Amino Acid Sequence
- Animals
- Antibody Formation
- Antigen-Antibody Reactions
- Antigenic Variation
- Epitopes / immunology
- Gene Products, env / genetics
- Gene Products, gag / genetics
- HIV Antibodies / immunology
- HIV Envelope Protein gp120 / immunology
- HIV Envelope Protein gp41 / immunology
- HIV-1 / immunology
- Humans
- Molecular Sequence Data
- Virus Replication
Citations
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