Treatment of HIV infection

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Editor, – I refer to 'New approaches in the treatment of HIV infection' by Dr Don Smith (Aust Prescr 1998;21:44-6).

In his presentation I read that 'Originally, it was thought that there was a long period of clinical and virological latency when very little was happening in an asymptomatic, but infected, patient ... we now know that there is no latent period in HIV disease.'

One of the regulatory genes of HIV, called nef (negative-regulatory factor),is a gene which slows down the transcription of the viral genome and may therefore be responsible for HIV remaining dormant in infected cells.

If so, is the presence of this gene and the analysis on latency period absence not contradictory?

I need further explanation on these two points.

Tadese Geleta
General Practitioner
Gimbie SDA Hospital
Ethiopia

Dr D. Smith, the author of the article, comments:
Dr Geleta questions the view that there is no period of virological latency in people infected with HIV disease given that HIV carries a regulatory gene (nef) that may be responsible for inducing latency in infected cells. This apparent contradictory information can be explained if the dynamics of HIV replication are considered. As HIV goes through its replication cycle, it must be remembered that this process is happening slightly differently in the large number of lymphocytes that are infected each day. The process is not perfect, and errors are made at each step. In general, however, the majority of cells that are infected are CD4 positive lymphocytes. The process of infection appears to activate these cells and thereby activate the ongoing replication of HIV. However, a small number of these T-cells become infected but fail to become activated and contribute to the pool of long-lived, latently infected T-cells. It is these cells that may rekindle HIV infection after discontinuing combination antiviral therapy. It has been estimated that possibly 1:8000 or 1:10 000 infected T-cells remains latently infected following infection with HIV.1

More recent information regarding the function of the nef gene seems to contradict its original role of a down-regulator of HIV replication. In fact, patients infected with HIV with a defective nef gene tend to show very low levels of viral replication and slow disease progression.2 Similarly, SIV with a defective nef gene seems to be less replication competent.3 These findings would imply that the nef gene is in fact important for up-regulating HIV replication.

This means that in an environment where hundreds of thousands of new virions are being produced and infecting cells, it is possible to see both high turnover replication rates and low levels of seeding inactivated cell lines giving both latency and acute active replication.

References

  1. Chun TW, Carruth L, Finzi D, Shen X, DiGiuseppe JA, Taylor H, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997;387:183-8.
  2. Learmont J, Tindall B, Evans L, Cunningham A, Cunningham P, Wells J, et al. Long-term symptomless HIV-1 infection in recipients of blood products from a single donor. Lancet 1992;340:863-7.
  3. Daniel MD, Kirchhoff F, Czajak SC, Sehgal PK, Desrosiers RC. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene. Science 1992;258:1938-41.