Mechanism of HIV Infection Identified

Mechanism of HIV Infection Identified

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Highlights
  • A research team carried out a study to identify how HIV overcomes the great barriers of the mucosal bottle neck to invade the body of the host.
  • Certain strains of the HIV 1 virus were 3 times more infectious and 1.4 times increased ability to replicate.
  • They were more resistant to IFN-alpha2 and IFN-beta of the immune system than other strains.
The AIDS virus has to overcome huge barriers, during an intercourse, to identify the target cell and to result in a new infection. The virus has to move past the genital mucosa and make its way through the epithelial cells that are tightly packed together and meant to keep invading infections away. Another considerable step in the path of the AIDS virus is to move past the immune system, which includes the type 1 interferons. Not every unprotected contact results in the development of a HIV infection, in fact only 1 in 1000 unprotected exposures has been found to result in a successful HIV-1 infection.
Mechanism of HIV Infection Identified

Dr. Beatrice Hahn,  professor of Medicine and Microbiology at the University of Pennsylvania wanted to identify what was unique about the transmission of these viruses that aided in their ability to infect. According to Dr. Hahn, the human body has many barriers that prevent the entry of viruses.

Therefore, Dr. Hahn and her research team studied the nature of these HIV-1 strains to determine how they successfully passed through the genital mucosa, which formed the boundary of entry for various micro-organisms. 

Studying Viral Isolates

The viral isolates from the genital secretions and blood of 8 donors with chronic HIV infection and their matched recipients were studied. The researchers identified a sub population of HIV- 1 strains which had biological properties that enabled them to efficiently cause new infections.  The results of the findings were published in a study in Proceedings of the National Academy of Sciences.

Findings of the Study

  • 300 virus isolates were identified by the research team from individual HIV-1 particles that were found to infect the donors as well as the matched recipients.
  • Recipient viruses were three times more infectious than viruses isolated form the donors.
  • The recipient viruses had a 1.4 increased ability to replicate.
  • They were significantly more resistant to the anti-viral effects of interferons, IFN-alpha2 and IFN-beta.
  • The transmitted viruses when compared to donor viruses needed an 8-fold higher concentration of IFN-alpha2 along with a 39-fold higher concentration of IFN-beta in order to be able to produce a 50% reduction in replication.
  • The odds of the strains of HIV that were found to be interferon-resistant, where the highest IFN-alpha2 and IFN-beta doses were 35-fold and 250-fold greater.
Shilpa Iyer, who is the doctoral student and the first author of the study stated that this means that the rapidly multiplying strains of interferon resistant HIV strains had higher transmission fitness. According to the author, this was confirmed pretreating CD4 immune cells with interferon before the virus was isolated. The donor isolates were thus selected based on whether they had a virus like phenotype.

The recipient isolates were found to be released from the infected CD4 cells more efficiently than the donor isolates. The important aspect of the transmission is the production of cell free particles.

Mucosal Bottleneck

The study was able to identify the factors of the virus that was able to overcome the mucosal bottleneck. The HIV-1 strains that were able to replicate and which were able to spread efficiently even when they were faced with a strong immune reaction were the ones that were successful in moving past the mucosal barriers.

Identifying the properties of the virus that was able to confer the ability to transmit the virus even though there were considerable barriers in the human body could be used in the development of treatment for HIV-1 infection. Dr. Hahn stated that they still do not know which of the viral gene products provided the resistance to interferon, but understanding these mechanisms will aid in providing new targets for AIDS prevention as well as therapy.

Primary HIV-1 Infection

The HIV-1 infection can occur through mucosal barriers or through inoculation. The dendritic cells are the first to attack the viruses when the HIV-1 binds to the receptors of the dendritic cells. At this stage, it was believed that the dendritic cells were antigen presenting cells that aided in priming T cells with raid infection of the T cells. 

Here are two separate sites of binding of the HIV 1 virus
  • The CD4+ T cell receptor
  • A 7-transdomain chemokine co-receptor.
The entry of the HIV-1 virus in to the cell then leads to the integration of the virus into the genetic material of the host. HIV-1 dissemination soon occurs to the CNS with rapid viral replication in actively infected cells. The time taken for viremia is 4-11 days, though the development of symptoms may take many days.

The initial infection of HIV-1 requires a highly dynamic relationship between virus and host. The symptoms that develop are associated with a large amount of virus in the body and the response of the host's immunological process. 

The identification of the exact mechanism that exists for the entry of certain strains of HIV into the body can be used to strengthen the immune system as well as develop new strategies for treatment. This would not only prevent the spread of infection but will also provide new targets for therapy.

References:
  1. Shilpa S. Iyer, Frederic Bibollet-Ruche, Scott Sherrill-Mix, Gerald H. Learn, Lindsey Plenderleith, Andrew G. Smith, Hannah J. Barbian, Ronnie M. Russell, Marcos V. P. Gondim, Catherine Y. Bahari, Christiana M. Shaw, Yingying Li, Timothy Decker, Barton F. Haynes, George M. Shaw, Paul M. Sharp, Persephone Borrow, Beatrice H. Hahn. Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness. Proceedings of the National Academy of Sciences, 2017; 201620144 DOI: 10.1073/pnas.1620144114
  2. Primary HIV Type 1 Infection - (http://cid.oxfordjournals.org/content/38/10/1447.full)
Source: Medindia

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