Diarrhea, in the context of human immunodeficiency virus
(HIV) infection, is an enormously important clinical issue (Smith et al., 1988). Diarrhea in patients with AIDS is
extremely problematic for both patient and clinician. More than 50% of AIDS
patients suffer from diarrhea, the cause of which is unexplained in most of the
cases. The causes of diarrhea in HIV infection are multifactorial. Chiefly,
these may be caused by the primary retroviral infection per se, several
opportunistic infections, alteration of gut microbiome, immune reconstitution,
water sanitation or as a complication of highly active anti-retroviral therapy
(HAART) like didanosine or ritonavir, and may also result from induced
pancreatic insufficiency (Haas et al., 2011; Saha et al., 2011; Murray and Rubio-Tapia, 2012; Vyas et al., 2012; Agholi et al., 2013; Martin et al., 2013; Clay and Crutchley, 2014; Dye, 2014; Dikman et al., 2015; Green et al., 2015; Rubaihayo et al., 2015; Yates et al., 2015). The diarrhea in primary HIV infection
is primarily secretory in nature (Juckett and Trivedi, 2011; MacArthur and DuPont, 2012). Some preliminary studies have suggested
the role of viral proteins in causation and aggravation of diarrhea in HIV
infected patients. For example, retroviral tat proteins have been demonstrated
to enhance myenteric neuronal excitability by altering different sodium
channels (Ngwainmbi et al., 2014). It is obvious that in HIV infection, a
viral specific protein that affects genomic transcription would affect diverse
cellular mechanism (s). This opinion piece advances a concept of how HIV may
gain entry into the gastrointestinal mucosa using an upstream neuropeptide
mechanism, providing a perspective of an incipient mechanism involved in
mucosal disease caused by HIV and potential druggable targets for HIV induced
diarrhea.
Namely, the hypothesis is based on two key reported
observations: (i) the molecular overlap of a pentapeptide belonging to gp120,
the key viral envelope protein that helps in cellular docking and a segment of
vasoactive intestinal polypeptide (VIP) (Pert et al., 1988). HIV have been variously reported to
bind to the VIP receptors, VPAC1 and VPAC2, and produce differential effects
(see below). (ii) The earliest observations from HIV infected patients of the
elevation of serum VIP during primary HIV illness and diarrhea (Manfredi et
al., 1993, 1994). Potentially, how primary mucosal HIV
infection causes elevation of serum VIP in not known. Here a rationale is
presented that has striking similarity to a mechanism similar toClostridium difficile diarrhea,
one which involves disruption of cytoskeletome of mucosal epitheliocyte
(Farrell and LaMont, 2000; Kumar et al., 2014). The tat proteins, through
transcriptional activation, may hijack and alter the cytoskeletal machinery,
thus resulting in leakage of cellular peptides like VIP (Vitale et al., 2013). This may also occur from submucosal
neurons which are rich in VIP (Vitale et al., 2013). It is well known that excessive VIP in
the mucosal extracellular space may cause secretory diarrhea (Krejs et al.,1980; Chambers et al., 2005), much like that seen in VIPoma (Krejs et
al., 1977). There are only scant reports which have
examined the electrolyte composition of diarrheal stool in HIV diarrhea or
examined mucosal flux of electrolytes by Ussing's chamber after retroviral
mucosal loading, but is generally agreed that it is of the secretory type
(Schiller et al., 1994; Stockmann et al., 2000; Nwachukwu and Okebe, 2008)...
Purchase full article at: http://goo.gl/US9mdc
By:
Edited by: Ghanshyam
Upadhyay, City College of New York-CUNY, USA
Reviewed by: Sandeep Kumar,
State University of New York College of Optometry, USA; Ravi C. Kalathur, New
York Structural Biology Center, USA
*Correspondence: Arun Chaudhury ; Email: moc.liamg@notsob.yruhduahcnura; Email: gro.hda@yruhduahc.nura
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