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The call for a cure was launched in February 2011 by the president-elect of the International AIDS society and Nobel Prize winner Françoise Barré-Sinoussi. The article by Lewin et al (2011) provides an excellent overview of possible promising strategies for cure using an ‘infectious disease model’ (sterilising cure model), in which HIV and all HIV-infected cells would be eliminated, or a ‘cancer model’ (functional cure model), in which there would be long-term health in the absence of treatment accompanied perhaps by low levels of HIV in the blood.

The three challenges to finding such a cure are:  (i) viral latency in resting CD4 cells (HIV lying low with its genes turned off, unaffected by antiretroviral drugs or host immune responses), (ii) residual viral
replication (with low amounts of HIV reseeding the blood stream), and (iii) reservoirs (hiding places such as the gastrointestinal tract, the brain, and the genital tract). Latently infected cells are rare (1 in 100,000 to 1 in a million) so using promising strategies such as the histone deactylase inhibitors used in cancer that could turn HIV genes on or cytokines that could activate latently infected cells to replicate so that antiretroviral therapy could take effect, may haveindiscriminate effects on uninfected cells since these therapies will no select for only infected cells. The potentials for side effect will therefore be a challenge. Gene therapy with zinc finger nuclease to reduce CCR5 expression and block HIV docking is another possibility and is currently being explored in some ongoing studies.

The famous ‘Berlin’ HIV-positive patient who was treated twice for acute myeloid lymphoma with a pre-transplantation conditioning regimen, including total body irradiation, followed by transplantation of stem cells from a special donor is a point in time study of the possibility of a HIV cure (Allers et al, 2011). This patient had to undergo bone marrow transplantation twice due to leukemia. That bone marrow stem cell donor was homozygous for the CCR5Δ32 deletion (i.e. both genes coded for this deletion), meaning that his or her HIV target cells did not allow HIV to complete docking after linking with the gp120 receptor. Donor-derived memory CD4 cells replaced the recipient’s cells reaching the normal range over a 2-year period and HIV has remained undetectable in gut tissue, brain, bone marrow mononuclear cells, and peripheral blood cells (residual viral replication sites). The patient remains susceptible to HIV infection
if he is exposed to CXCR4-tropic HIV. It is impossible to analyse every cell in living humans so proving viral eradication is impossible. However, given that HIV has not reappeared after 3 years without antiretroviral therapy, the authors conclude that a cure has been achieved. With stem cell transplantation carrying a mortality of up to 30%, this procedure is not practical but this story does give hope that one day we will find a cure for HIV.

While we wait and hope for a cure in our lifetime, universal access to antiretroviral treatment remains top priority and an agenda for all nations in view of the evidence to show that treatment could also serve as a prevention tool. These are early days to be talking about a cure. But community engagement in this basic/clinical science challenge is key—this is one prize we need to keep our eye on.

(Adapted from the edits of Cate Hankins – Scientific Adviser for UNAIDS and Editor for HIV This week – Issue 91)

References:
1. Lewin SR, Evans VA, Elliott JH, Spire B, Chomont N. Finding a cure
for HIV: will it ever be achievable? J Int AIDS Soc. 2011 Jan 24;14:4.
2. Allers K, Hütter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E,
Schneider T. Evidence for the cure of HIV infection by CCR5Δ32/Δ32
stem cell transplantation. Blood. 2011 Mar 10;117(10):2791-9

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