“Fusion and binding inhibition” key target for HIV-1 treatment and pre-exposure prophylaxis: targets, drug delivery and nanotechnology approaches

Figures & data

Table 1. Description of host cell receptors involved in HIV-1 transmission.

Receptor	Basic details	Mechanism involved
CD4 + T cells	The primary receptor for HIV-1 is CD4 to infect T cells, macrophages. These are dispersed throughout the lamina propria of the human vagina, ectocervix and endocervix.	These cells become activated when they are presented with peptide antigens by MHC (Major Histocompatibility Complex) class II molecules, which are expressed on the surface of antigen-presenting cells (APCs). Upon activation CD4 T cells undergo a series of division to produce helper T cells (TH) and memory T cells (TM). TM cells remain in reserve whereas TH cells secrete a variety of cytokines. Some of these co-express high level of both CCR5 and CXCR4 co-receptors (Veazey et al., 2003).
Dendritic cells	Dendritic cells (DC) are located just beneath the endocervical columnar epithelium.	HIV-1 envelope (Env) interacts with DCs via a number of attachment factors. The C-type lectin receptors such as DC-SIGN (Geijtenbeek et al., 2000), mannose receptor, langerin (expressed on Langerhans cells) and DCIR are some of the best-described mechanisms of HIV capture by DCs. GM3 is a glycosphingo-lipid called gangliosides promotes their specific recognition by DCs. Siglecs, a family of proteins including membrane gangliosides. Increased Siglec-1 expression on the surface of DCs, enhanced HIV uptake by mature DCs (Sedwick, 2012).
Langerhans cells (LCs)	These are a DC subtype residing within the outer squamous epithelium of the skin or mucosa. HIV-specific receptors are expressed by these LCs, including CD4, CCR5 and the C-type lectin langerin (CD207), but not CXCR4.	Antibodies that bind CD4 and CCR5 partially block the uptake of R5-tropic HIV-1 by LCs (Hladik et al., 2007). LC serves detecting HIV-1 entry into the vagina, through C-type lectin receptor (CLR), Toll-like receptor (TLR) and other recognition receptors (Chang & Altfeld, 2009). The entry by the assistance of Langerhans cell solely depends on the activation status of the LC. As immature LCs prevent HIV-1 infection by clearing invading HIV-1 through the C-type lectin langerin but blocking langerin function by high virus concentrations enables HIV-1 transmission by LCs (Nishibu et al., 2006).
Macrophages	Macrophages in the female genital tract constitutively express CCR5 during the period of activation and emigration from the mucosa.	These are professional APC, triggering antibody responses by the presentation of pathogen derived peptides via the MHC-II pathway to CD4+ T cells and activating CD8+ cytotoxic T-cells (CTL) by cross-presentation of HIV-1 antigens. Since macrophages secrete cytokines that recruit T lymphocytes to sites of infection. They can “support” establishment of viral infection by enlarging the number of primary target cells (Ackerman & Cresswell, 2004). An infected macrophage can infect at least one T cell every six hours for many weeks (Groot et al., 2008).
Galactosylceramide (GalCer)	It is now well established that HIV infection in CD4-negative cells follows some alternate routes for several cell types. Mentioning epithelial cells as target for HIV-1, the mechanism proposed for its transmission through CD4-negative cell involves a specific receptor, i.e. glycosphingolipid galactosylceramide (GalCer) (Delézay et al., 1996; Nittayananta et al., 2016).	Cell lines showed that virus uses its surface envelope glycoprotein gp120 to get access via cells of epithelial origin. HIV-1 also exploits heparan sulfate proteoglycans (HSPGs) receptors for attachment purpose.
Heparan sulfate proteoglycans (HSPGs)	These HSPGs consist of a core protein and unbranched anionic chains composed of repeating disaccharides units (sulfated uronic acid and hexosamine residues).	Mechanism involved with this receptor can be explained by the role of negatively charged sulfated groups of heparan sulfate (HS) chains in the virus attachment to the host cell surface (Lindahl, 2007; Rusnati et al., 2009).

Figure 1. Transmission of HIV-1 virus.

Figure 2. Targets for fusion and binding inhibition.

Table 2. List of polymers used for the formulation of mucoadhesive vaginal gel formulation system.

Polymer	Properties	Market products
Polycarbophil	Low irritation and toxicity, non-sensitizing, good stability, eliminate the effect of vaginal discharge which shortens the residence time of vaginal formulations.	Miphil (acid buffer), Replens® (with carbopol 974p)
Carbopol (974p, 934p, 940p)	Good buffering capacity (around pH 4), nontoxic and nonirritating, Vaginal fluid’s dilution may provide better wetting of polymer and hence formation of stronger mucoadhesive bonds and prolongation of the residence time.	Miphil (acid buffer), Advantage-S® (Carbopol 974p with polycarbophil), Replens® (Carbopol 974p with polycarbophil)
Carrageenan	Combination of (kappa and lambda) has proved topical microbicide, relatively nontoxic and nonirritating, for topical application, Kappa carrageenan also acts as absorption inhibitor.	Carraguard™, PC-815 gel combining Carrageenan with MIV-150, PC-515 gel
Chitosan	Nontoxic and nonirritating, biocompatible with both healthy and infected skin, useful as a carrier for longer release.	Chitosan based metranidazol vaginal mucoadhesive gel
Cellulose derivatives HEC, HPC, HPMC, Na-CMC	A wide versatility of mucoadhesion, and viscosity ranges is available. Nontoxic and nonirritant.	Conceptrol® (Na-CMC), K-Y® (HEC), Gynol-II, (Na-CMC), Ushercell (HEC), Monocaprin hydrogel (HPMC)
Sodium-alginate	Compatible for vaginal use, and already tried for N-9 formulation	Delivery gels were alginate crosslinked with calcium chloride containing 3% N-9 and were manufactured over a pH range of 3.4–5.9
Polyacrylic acid	These polymers are the most investigated bioadhesive polymers for vaginal applications	BufferGel™, Acidform™ gel
Pectin, gum acacia and tragacanth	Nontoxic, nonirritating and already used in vaginal formulation	Aci-Jel (gum acacia and tragacanth)

Figure 3. Nanotechnology tools that can be exploited for the rational delivery of fusion inhibitors.

Figure 4. Cyclodextrins and polymeric micelle as nanodrug delivery systems.

Figure 5. Logical assessment of the best inhibition target with respect to HIV viral load.

Veazey RS, Marx PA, Lackner AA. (2003). Vaginal CD4+ T cells express high levels of CCR5 and are rapidly depleted in simian immunodeficiency virus infection. J Infect Dis 187:769–76

 PubMed Web of Science ®Google Scholar

Geijtenbeek TB, Kwon DS, Torensma R, et al. (2000). DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100:587–97

 PubMed Web of Science ®Google Scholar

Sedwick C. (2012). How HIV sneaks aboard mature dendritic cells. PLoS Biol 10:e1001454

 PubMed Web of Science ®Google Scholar

Hladik F, Sakchalathorn P, Ballweber L, et al. (2007). Initial events in establishing vaginal entry and infection by human immunodeficiency virus type-1. Immunity 26:257–70

 PubMed Web of Science ®Google Scholar

Chang JJ, Altfeld M. (2009). TLR-mediated immune activation in HIV. Blood 113:269–70

 PubMed Web of Science ®Google Scholar

Nishibu A, Ward BR, Jester JV, et al. (2006). Behavioral responses of epidermal Langerhans cells in situ to local pathological stimuli. J Invest Dermatol 126:787–96

 PubMed Web of Science ®Google Scholar

Ackerman AL, Cresswell P. (2004). Cellular mechanisms governing cross-presentation of exogenous antigens. Nat Immunol 5:678–84

 PubMed Web of Science ®Google Scholar

Groot F, Welsch S, Sattentau QJ. (2008). Efficient HIV-1 transmission from macrophages to T cells across transient virological synapses. Blood 111:4660–3

 PubMed Web of Science ®Google Scholar

Delézay O, Yahi N, Fantini J. (1996). Detection of functional galactosylceramide (GalCer) receptors on CD4-negative HIV-1 target cells. Perspect Drug Discov Des 5:192–202

 Google Scholar

Nittayananta W, Weinberg A, Malamud D, et al. (2016). Innate immunity in HIV‐1 infection: epithelial and non‐specific host factors of mucosal immunity – a workshop report. Oral Dis 22:171–80

 PubMed Web of Science ®Google Scholar

Lindahl U. (2007). Heparan sulfate-protein interactions – a concept for drug design? Thromb Haemost-Stuttgart 98:109

 PubMed Web of Science ®Google Scholar

Rusnati M, Vicenzi E, Donalisio M, et al. (2009). Sulfated K5 Escherichia coli polysaccharide derivatives: a novel class of candidate antiviral microbicides. Pharmacol Ther 123:310–22

 PubMed Web of Science ®Google Scholar