Plenary Lecture: HIV dynamics and Load: Implications for Therapy and Eradication

Dr. John Mellors, et al

This plenary presentation gave a good overview of HIV replication during the asymptomatic phase of the infection. Although there are only low levels of infectious HIV, virus is being made and removed very rapidly. An analogy would be a rushing stream, only a small amount of water at any one point but a lot of water passing by. This rapid virus production throughout the asymptomatic phase of HIV has two major implications.

1. An antiviral therapy, which is able to stop virus production, will have a profound effect on disease progression.
2. The potential for virus resistance creates a formidable challenge.

For the technically minded: about 10¹⁰ virions are produced each day; free virion half-life, 0.19 day; infected lymphocyte, half life 2.2 days; generation time, 2.5 days to give about 140 generations of virus replications per year; 10⁹ to 10¹⁰replication cycles per day; mutation rate, 3x10^-5/bp per cycle.

These factors lead to the conclusion that antiviral therapies, that give only partial control of HIV replication, are doomed to eventual failure. Each 10-fold (log) reduction in viral load has been estimated to lower the risk of clinical progression by 65%. Therefore, therapy should aim aggressively for a complete stop in replication:

1. Raise the "genetic barrier" Mutations at active catalytic site will tend to reduce the viability of the virus. Select drug combinations (e.g., AZT/3TC) with mutually exclusive resistant strains.

2. Rational drug combinations Consider both targeting the same viral enzyme with 2 drugs and targeting different viral enzymes. Triple therapy can give dramatic reduction in viral load for more than one year.

3. Continual viral suppression, say two or three times a day, is not good enough -- that gives the virus two or three chances a day to become resistant. Continuous viral suppression, giving full 24 hour cover every day, is essential.

Virus load as a prognostic factor.

Higher virus load is correlated with:

• higher rate of loss of CD₄cells
• higher risk of CD₄decline
• higher risk of progression to AIDS
• higher risk of death

However, CD₄ cell count is an independent prognostic factor. J Cuffin (XI International Conference on AIDS, Vancouver, 1996) suggested an analogy, a train heading for rocks on the track. The speed of the train represents the viral load, the distance from the rocks represents the CD₄ cell count. The lower the speed (viral load) and the greater the distance (CD₄cell count) the better the prognosis.

Cure?

Complete eradication of HIV unlikely, but avoiding progression to AIDS for prolonged time with continuous therapy is becoming a real possibility.