The Ultimate HIV Sanctuary
Profaning the ultimate HIV sanctuary is the nice title given by Didier Trono to an interesting editorial (1) in ‘Cell Host & Microbe’ describing recent findings from Kathleen Collins group on the mechanisms how HIV infects multipotent hematopoietic stem cells (2). These data, if confirmed, demonstrate that HIV cure will be an even more formidable challenge than initially thought.
Quiescent T cells have long been known to represent the quantitatively most important latent HIV reservoir. Last year, Kathleen Collins and her group (3) reported that HIV-1 could infect and kill multipotent hematopoietic progenitor cells (HPCs). They also reported that in a fraction of these cells, infection led to latent proviruses, the expression of which was reactivated by myeloid differentiation.
In this new study, they now demonstrate that not all HIV strains can infect early blood progenitors but that only X4 viruses have this ability.
Even in highly viremic individuals, the percentage of infected hematopoietic stem cells (HSCs) appears to be low, from 2 to 40 genomes per 10,000 CD34+ cells.
However, an important question remained: were HIV-infected CD34+ cells just early hematopoietic progenitors with a finite life span or true stem cells capable of multipotent self-renewal?
This is where the new study comes.
The authors used a replication-defective, GFP-expressing HIV-derived lentiviral vector coated with an X4-tropic HIV-1 envelope. This construct is non-cytopathic and express GFP (Green Fluorescent Protein), which helps tracing its outcome. The use of this replication-defective HIV construct allows studying the development of all infected HPCs, without viral killing of some sub-population after infection.
In vitro, X4-tropic Envs had the capacity to infect multipotent HPCs, whereas R5-tropic Envs primarily infected more mature HPCs.
AMD300, a CXCR4 antagonist, was able to reduce the rate of infection in total HPCs and nearly eliminated infection in CD34high CD133+ cells, which represent primitive HPCs. In contrast, Maraviroc, a CCR5 inhibitor, did not impede infection of these cells.
The next experiment used the mouse xenograft system. After exposing bone marrow-derived CD34+ cells to this viral construct, the cells were transferred into NOD/SCID IL-2Rgammanull mice. Among 7 mice successfully engrafted, 5 carried in their peripheral blood GFP+ cells of both myeloid and lymphoid lineages for at least 20 weeks. Since only true HSCs can maintain multilineage reconstitution, these data show that cells with multipotent self-renewal capacity had been effectively transduced.
Consequently HIV is able to infect HSCs, but gene expression is not induced until they differentiate into more mature progenitors. HSCs undergo asymmetric division, where a daughter cell becomes a committed progenitor while the other remains a multipotent hematopoietic stem cell. Consequently, this reservoir can be maintained life long.
A clinically essential correlate of these findings is that only patients harboring X4 or R5/X4 dual tropic HIV strains should have HIV-infected HSCs. This could be reassuring information, meaning that this theoretically inexpugnable HIV reservoir would only occur late in the course of HIV infection and could be prevented by early initiation of ART.
1-Trono D, Marzetta F. Profaning the Ultimate Sanctuary: HIV Latency in Hematopoietic Stem Cells. Cell Host & Microbe 2011; 9 (3): 170-2
2-Carter CC, McNamara LA, Onafuwa-Nuga A et al. HIV-1 Utilizes the CXCR4 Chemokine Receptor to Infect Multipotent Hematopoietic Stem and Progenitor Cell. Cell Host & Microbe 2011; 9 (3): 223-34
3-Carter CC, Onafuwa-Nuga A, McNamara LA, et al. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nat Med. 2010; 16 (4): 446-51
Key words: HIV reservoir, hiv cure, hiv eradication, hiv persistence, hiv stem cells