398
Systems biology approaches are providing new clues into host-pathogen interac-
tions and help our understanding of the contributions made by innate and adaptive
immune defenses to prevent limit infection with HIV and limit disease progression.
This will be critical for developing novel approaches to HIV prophylaxis and ther-
apy by validating new biomarkers predictive of disease outcome and treatment effi -
cacy (Peretz et al. 2012 ).
Drug-Resistance in HIV/AIDS
Drug-resistance is a critical factor contributing to the loss of clinical benefi t of cur-
rently available HIV therapies. Accordingly, combination therapies have been used
to address the rapidly evolving virus. However, there has been great concern regard-
ing the growing resistance of HIV-1 strains to current therapies as multidrug resis-
tance to protease inhibitors is becoming more common.
HIV protease inhibitor (PI) therapy results in the rapid selection of drug resistant
viral variants harboring one or two substitutions in the viral protease. To combat PI
resistance development, two approaches have been developed; (1) to increase the
level of PI in the plasma of the patient; and (2) to develop novel PI with high potency
against the known PI-resistant HIV protease variants. Both approaches share the
requirement for a considerable increase in the number of protease mutations to lead
to clinical resistance, thereby increasing the genetic barrier. Nevertheless, HIV can
use an alternative mechanism to become resistant to PI by changing the substrate
instead of the protease. Increased polyprotein processing due to mutations in the
natural substrate of the HIV protease might be a new mechanism by which HIV can
become resistant to PIs. This enables HIV to develop PI resistance without the need
for multiple changes in its protease and thus avoids the high genetic barrier to resis-
tance that new PIs provide.
The level of resistance to antiretroviral drugs differs among HIV variants. There is
limited knowledge of resistance mutations in non-B subtypes of HIV type 1 (HIV- 1)
and their clinical relevance, despite the fact that >90 % of patients with HIV-1 infec-
tion worldwide have non-subtype B variants of HIV-1 (Wainberg et al. 2011 ). Most
reports on drug resistance deal with subtype B infections in developed countries.
The development of resistance is driving research to identify new drugs targeting
novel steps in the HIV-1 replication cycle. Progress has been made in developing
drugs targeting HIV-1 entry, integration and maturation. The addition of new drugs
to the existing therapeutic arsenal will improve treatment options and clinical pros-
pects particularly for those patients failing current drug regimens based primarily on
combinations of reverse transcriptase and protease inhibitors. Despite the negative
impact of drug resistance in the clinic, understanding resistance mechanisms pro-
vides a powerful tool to aid the discovery and development of new HIV-1 therapies.
The large number of therapy options makes it diffi cult to select an optimal ther-
apy, particularly in patients that develop resistance to some drugs. Computer-based
therapy selection, which assesses the level of viral resistance against drugs, has
become a mainstay for HIV patients as shown in Fig. 11.3.
11 Personalized Management of Infectious Diseases