1. Kendra McAlister
VME 158
Disease Resistance in HIV-1 Exposed Seronegative Individuals
HIV-1 and HIV-2 are the two strains of the human immunodeficiency virus
(HIV) that can culminate into acquired immunodeficiency syndrome (AIDS); both
share similar modes and routes of transmission as well as clinical manifestations
that can become increasingly fatal as immunodeficiency progresses (Nyamweya et
al. 2013). HIV is generally transmitted through contact between infected bodily
fluids (i.e. genital secretion, blood and breast milk) and mucosal tissue of the body
(Kelly 2009). Genital mucosal tissue is the most common site of infection, leading to
over 80% of infections worldwide (Kelly 2009). HIV-1 and HIV-2 are derived from
different simian to human transmission events; HIV-1 came from the SIVcpz strain
of the simian immunodeficiency virus (SIV) and HIV-2 originated from SIVsmm
(Nyamweya et al. 2013). Transmission from simians to humans likely went
unnoticed for a length of time, but due to sociopolitical disruptions in the late 20th
century there were several outbreaks of AIDs in Africa (University of Arizona 2004).
Increased global travel and changing sexual practices facilitated the dispersal of HIV
from Africa to other continents (University of Arizona 2004). HIV infection presents
an alarming challenge for public health professionals across the globe as a vaccine is
currently unavailable and the expected annual incidence of infections caused by
HIV-1 alone is 2.7 million cases (Nyamweya et al. 2013). HIV-1 is often the focus of
research and health campaigns charged with mitigating the impact of infection on
high risk populations. Compared to HIV-2 infection, HIV-1 progresses to
immunodeficiency much more quickly and has a much broader geographical reach
(Nyamweya et al. 2013).

2. Kendra McAlister
VME 158
Considering HIV-1’s greater capacity for infectivity, some researchers have
made attempts to analyze the genetic and immunologic potential of individuals who
remain seronegative in spite of varying levels of HIV-1 exposure. These hosts, often
referred to as HIV-exposed seronegative individuals (HESNs), have numerous
mechanisms for combating and reducing the risk of HIV-1 infection (Taborda-
Vanegas, Zapata, and Rugeles 2011). Regarding their genetic characteristics, the
most common genetic factor identified across cohorts was the existence of different
CCR5 gene variants (Taborda-Vanegas, Zapata, and Rugeles 2011). In particular, the
CCR5-delta 32 (CCR5- 32) mutation, found in about 10% of Caucasians, results in
altered protein expression, reducing the size of the CCR5 protein and removing it
from the surface of immune cells (Taborda-Vanegas, Zapata, and Rugeles 2011).
Without this protein on the cell surface HIV-1 is unable to bind and infect the host.
Although people with homozygote expression of this CCR5 mutant are highly
resistant to HIV-1 infection, this mutation only explains 3.6% of HESNs (Taborda-
Vanegas, Zapata, and Rugeles 2011). This suggests that there are likely other
mechanisms, genetic or immunological, that endow certain HESNs with disease
immunity. In addition to the CCR5- 32 mutant, HESNs who used intravascular drugs
in Southeast Asia were discovered to have “a guanine to adenine substitution in the
316 position of the CCR5 gene”, affecting cellular expression of CCR5 and thus
inhibiting HIV-1 infection (Taborda-Vanegas, Zapata, and Rugeles 2011). Perhaps
there are other CCR5 variants or unique genetic mechanisms that serve as
deterrents to HIV-1 infection in other groups of HESNs.

3. Kendra McAlister
VME 158
Regarding the immunologic factors that help in evading HIV-1 infection, the
innate immune system represents “the first line of defense against infection and
consists of” cells, such as Toll-like receptors (TLRs), that are able to respond to
pathogens via pattern recognition receptions (PRRs) (Chang and Altfeld 2010).
“Stimulation of [Toll-like receptor 7/8] induces the production of several antiviral
and immunomodulatory cytokines” (Chang and Altfeld 2010), including interferon
(IFN) a, which has been shown to induce apoptosis in HIV-1 infected immune cells
as well as inhibit HIV-1 replication (Taborda-Vanegas, Zapata and Rugeles 2011).
The inhibitory effects of IFN-α expression have been studied in “macrophages,
monocytes, and humanized mouse models of HIV-1 infection” (Chang and Altfeld
2010). IFN- α is able to reduce viral duplication by mitigating “the formation of late
reverse transcriptase products in infected cells” (Chang and Altfeld 2010). “This
may be a consequence of IFN-αdependent up-regulation of “(Chang and Altfeld
2010) certain soluble factors, such as APOBEC3G, an enzymatic protein that is
capable of decreasing HIV-1 replication by modifying HIV-1 reverse transcripts
(Taborda-Vanegas, Zapata and Rugeles 2011), “leading to the degradation of HIV-1
encoded DNA” (Chang and Altfeld 2010). HESNs, namely commercial sex workers
(CSWs) have been shown to have a higher expression of IFN—α compared to health
controls (HCs), suggesting that the interferon may (Taborda-Vanegas, Zapata and
Rugeles 2011) “contribute both to viral control, inhibiting viral replication via
intracellular mechanisms, and to the initiation of the adaptive antiviral immune
response” (Chang and Altfeld 2010).

4. Kendra McAlister
VME 158
The second component of host immune response is the adaptive immune
system, which is usually mediated by innate immune response and becomes active if
the pathogen manages to evade or overcome innate immune activity (Chang and
Altfeld 2010). The adaptive, or acquired, immune response represents one of the
most important defenses against HIV-1 infection. While immune activation is
necessary to generate an effective attack on viral particles “activation of infected
cells induces replication” (Taborda-Vanegas, Zapata and Rugeles 2011). So targeted
immune activation is necessary to both effectively eliminate HIV-1 at the mucosal
site of entry and maintain a low basal level of activation to prevent the virus from
reproducing (Card, Ball and Fowke 2013). Mechanistically, expression of regulatory
T cells has been show to suppress T cell activation, thus limiting the number of HIV
target immune cells available for virus replication (Card, Ball and Fowke 2013).
Additionally, low levels of proinflammatory cytokine and chemokine production in
mucosal regions of the body reduce inflammatory response, also mitigating the
number of HIV target cells at the mucosal site of entry (Card, Ball and Fowke 2013
HESNs were shown to have both high regulatory T cell expression as well as low
levels of cytokines and chemokines, suggesting that low activation and susceptibility
to viral replication contributed to their resistance to HIV-1 infection (Taborda-
Vanegas, Zapata and Rugeles 2011).
Although HIV-1 infection presents a challenge to global health professionals
there are signs that certain communities of HESNs possess genetic and immunologic
ways of combating infection at the mucosal site of entry. In terms of genetic

5. Kendra McAlister
VME 158
components, CCR5 Δ32 polymorphism appears to confer disease resistance in at least
some Caucasians and Southeast Asian intravascular drug users. More studies should be
conducted to determine if there are other notable gene polymorphisms that offer a similar
level of protection against HIV-1 infection. Additionally, IFN-α expression in HESNs
contributes to the death of infected immune cells and helps to reduce viral
replication, offering two solid methods of viral control before the virus is about to
trigger activation of the adaptive immune response. However, even if the virus is
able to dodge innate immune activity, the acquired immune system, though
expression of regulatory T cells and limited production of cytokines and chemokines
is able to reduce susceptibility to infection and prevent the virus from replicating by
limiting its access to immune cells at the mucosal site of entry. Going forward,
researchers may be able to use these immunologic and genetic factors that provide
disease resistance in HESNs to develop better drugs and treatments for populations
that are at the greatest risk for HIV-1 infection.
References
Card, C. M., T. B. Ball, and K. R. Fowke. 2013. Immune quiescence: a model of
protection against HIV infection. Retrovirology 10: 141.
Chang, J. J. and M. Altfeld. 2010. Innate Immune Activation in Primary HIV-1
Infection. The Journal of Infectious Disease 202: 297 – 301.
Kelly, M. 2009 Natural history of HIV Infection. HIV Management in Australasia: a
guide for clinical care. 37 – 48.
Nyamweya, S., A. Hegdus, A. Jaye, S. Rowland-Jones, K. L. Flanagan, and D. C.
Macallan. 2013. Comparing HIV-1 and HIV-2 infection: Lessons for vial
immunopathogenesis 23: 221 – 240.

6. Kendra McAlister
VME 158
Taborda-Vanegas, N., W. Zapata, and M. T. Rugeles. 2011. Genetic and
Immunological Factors Involved in Natural Resistance to HIV-1 Infection. The
Open Virology Journal 5: 35 – 43.
University of Arizona. 2004. HIV Impacts. Retrieved from
http://www.biology.arizona.edu/immunology/tutorials/AIDS/impacts.html.