do they multiply as they do during inflammation?? and which subset does the most CD8 or CD4?

Thanks John. The question is whether proliferation of lymphocytes allow integration of HIV in the host genome (as without PHA stimulation the p24 levels are considerably low) or proliferation of these cells and rapid antigen presentation may lead to activation of macrophages and increased clearance of virus. Hence, whether their action of induced proliferation may be pathogenic or therapeutic. This definitely depends on the size of viral innoculum. Some mammalian C-type lectins such as SP-D and galectins are known to inhibit proliferation of PHA induced T lymphocytes. What could be their role in HIV infection?

I am grateful John, these papers have broadened my horizon on the subject.

PHA mediated activation of T cells need not necessarily enhance HIV entry. I presume you see a lot more p24 upon activation of T cells because integrated HIV also transcribes along with the clonal expansion of T cells. Antigen presentation and clearance may not be that high because, HIV-1 nef and Vpu are able to downmodulate MHC complexes involved in Ag presentation.

As to the question of HIV-1 integrating into the host cell genome because of proliferation..., Lentiviruses can infect and integrate into non-dividing cells while other retroviruses can infect cells that are dividing only. So lymphocyte proliferation would only serve to actively transcribe and translate integrated HIV-1 and need not enhance the integration process itself.

Thanks Sanath for joining in. You are right in saying that integration does happen in non-dividing cells as well and increased cell proliferation means increased viral replication. However, PHA mediated activation of T cells may lead to increased expression of HIV receptor CD4 and co-receptors CXCR4 and CCR5 and thus may influence the entry as well.

@John, T-cell activation is required for HIV-1 infection and this was established in 1989 in vitro. In vivo is not clear yet, although it has been proposed that HIV-1 by itself could help activate T-cells. Although, resting T cells could be infected too in vivo. The in vivo theory is not clear because of low HIV-1 specific T cells, absence of effectiveness of NK cells in response to HIV-1 infection, and absence of a positive correlation between viral load and cytokine stimulation at the initial infection phase. After the first infection is complete, HIV-1 produces multiple copies of itself, activates further T cells and essentially, creates its targets as it goes.

@ Taruna, I just looked up a few articles and sorry about my earlier statement. Activation of T cells is required for integration 'In vitro'. So, true PHA mediated activation in vitro will lead to higher integration events. But, integration is different from entry and increase in surface expression of receptors will definitely enhance entry. The point to note here is PHA mediated activation of T-cells causes proliferation of T cells and need not result in increased expression of receptors within 'a' cell. If PHA does increase receptor levels at the single cell level, then as you said, entry will be enhanced. Good point. Thanks for catching me on that.

In an HIV+ culture, PHA mediated stimulation will allow HIV-1 to replicate more robustly. Also, it will provide for activated T cells which can allow entry of the new viruses being produced. Additionally, the infected T-cells would also be expanded clonally to produce more infected T-cells. That would lead to exponential increase of p24 levels.

@ John, the experiment you suggest is extremely interesting. And it might be feasible too. I do not know how relevant it might be though. There is a round about way of quantifying this with some HIV-1 basic virology tools. If you interested, we could discuss it. Basically, you could activate the infected cells with PHA, wash it after some time and mix it with labelled T cells that have been activated or not activated. You could quantify p24 levels in the initial infections and the changes in the label in the mixed cells. By varying the four variables here, you could quantify it.

The initial infection usually occurs with inflammation. But the primary cells recruited to sites of inflammation are macrophages and indeed, HIV-1 has two flavors of Envelope. the R5 and X4 tropic viruses. R5 are macrophage tropic and a few T-cells express CCR5 too. Initially R5 viruses infect macrophages and transmit them to T-cells. X4 viruses are not very efficient at being trasnmitted. R5 tropic viruses seem to fare much better at transmission. Among HIV-1+ patients, the common initial infection is R5 tropic virus. Microenvironment might be better because there are other inflammatory responses being signalled by macrophages.