Download Prospective Treatments to manage HIV “viral reservoirs” reducing

Prospective Treatments to manage HIV “viral
reservoirs” reducing Viral Rebound once HAART
is discontinued
Viral Rebound and HAART
Though a patient’s HI viral load can be stably reduced to undetectable levels with the
prolonged administration of Highly Active AntiRetroviral Treatment (HAART), inevitably
viral-rebound occurs once HAART is discontinued1. HAART, which is a combination
therapy consisting of several antiretroviral drugs, can only prevent virioid production by
direct inhibition of several highly specific endogenous cellular mechanisms that the HI
virus utilizes to produce more virus particles. Though viral integration into the host
genome is fundamental in the HI viral infection cycle- with the eventual production of
more virions; when viral DNA integrates into the cellular genome and does not produce
more virions, the virus is said to have gone lytic within that cell.
HIV Tropism and the ‘Viral Reservoir’
The HI virus can infect all cells of the immune system that express CD4+ receptors,
amongst others, on their external membranes. The CD4+ receptor acts like a molecular
key, which allows viral recognition and entry into these CD4+ cells. It has now been
found that the broad-scale tropism of the HI virus is what leads to viral rebound once
HAART is stopped1,2.
Once long-lived cells of the immune system i.e. macrophages and resting CD4+ memory
T cells, which together form the most important sources of stable viral harboring, are
latently infected with the HI virus and escape exocytosis; the virus is effectively hidden
from the killing effects of HAART. This is due to viral incorporation -within the genomes
of these cells- but the lack of virion production, and an effective target for HAART. These
‘viral reservoirs’ then cause viral rebound and the lytic spread of the virus once HAART
is stopped.
Interestingly, despite the well established role of long-lived cells of the immune system
and the roles they play as viral reservoirs which lead to viral rebound, it has now been
found that infected, activated macrophages actually cause apoptosis of uninfected T
cells and protect infected T cells from apoptosis3.
Novel Approaches to managing ‘Viral Reservoirs’
Several recent studies have alluded to the need for the development of therapies that
minimize, and it is hoped eventually eliminate, these viral reservoirs, to allow for the
perpetual eradication of viremia following HAART.
Managing activated, infected, macrophage-associated reservoirs
A first prospective treatment involves the reduction of activated, infected macrophages,
an important viral reservoir. This therapy involves the selective disabling of
macrophages with the use of modified erythrocytes containing bisphosaphate
clodronate1- known as Clod-loaded RBC (red blood cells). Clodronate, which transiently
suppresses macrophage function, would be selectively administered to macrophages by
exploitation of their phagocytic role in the breakdown of erythrocytes. The attractiveness
of using erythrocytes as a vehicle for macrophage delivery of clodronate is that, firstly,
erythrocytes are highly abundant, secondly, they are completely biodegradable and
biocompatible; and lastly, they would allow for sufficiently-therapeutic quantities of the
drug to be specifically delivered to macrophages, when phagocytosed by macrophages.
Managing CD4+ memory T cell-associated reservoirs
The second of these prospective treatment-strategies involve the reduction of the most
noteworthy viral reservoir i.e. latently infected resting memory T cells. Memory T cells,
which can survive for decades,4 maintaining a stable viral reservoir, have been found to
pass on viral DNA to progeny cells via mitosis. Here the concentration of the cytokine,
IL-7- a hematopoietic growth factor responsible for lymphoid differentiation- has been
found to be quantitatively proportional to the number of latently infected resting memory
T cells5. Once HAART has been administered and a patient is aviremic, the use of
chemotherapy-like treatments, which until now have been used to treat various
leukemia’s, could be used to prevent further self-renewal of these memory T cells, by
making them visible to the immune system.
Conclusion
Though HAART is exceedingly proficient at the continued maintenance of untraceable
levels of HIV, HAART needs to be administered in combination with new approaches
and treatments to stamp out viral reservoirs. Only once virioid production can be
completely inhibited, and this can be combined with the removal or deactivation of
integrated viral DNA within host cells, to prevent viral rebound, can there be any hope of
complete and perpetual aviremia, with the eventual halting of HAART altogether.
References
1
Serafini S et al. Effect of macrophage depletion on viral DNA rebound following antiretroviral therapy in
a murine model of AIDS (MAIDS). Antiviral Research 81 (2009). Pg. 93- 102.
2
Chun T and Fauci A. Latent reservoirs of HIV: Obstacles to the eradication of virus. PNaS. USA (1999).
Pg. 10958- 10961.
3
Mahlknecht U et al. Resistance to apoptosis in HIV-infected CD4+ T Lymphocytes is mediated by
macrophages: role for Nef and immune activation in viral persistence. Journal of. Immunology. 165, pg
6437- 6446.
4
Riou C et al. Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives
the survival of CD4+ central memory T cells. Journal of Experimental Medicine 204 (2007). Pg 79- 91
Se’kaly RP et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic
proliferation. Nature Medicine- advance online publication (2009).
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