HIV-1 disease progression

Advanced techniques enable researchers to detect viral RNA and early immune responses within the first few weeks of HIV-1 infection (McMichael et al., 2010). This period is associated with impaired early innate immune responses and damage to the genital mucosa due to viral cytopathicity (McMichael et al., 2010).

Viral RNA can be detected 7 to 21 days after HIV-1 transmission and this period is known as the “eclipse phase” and refers to the time from virus entry into a cell to production of new virions (Figure 1.7) (Cohen et al., 2011; Haase, 2011; McMichael et al., 2010). During this time, virus replicates exponentially in the mucosa, submucosa and draining lymphoreticular tissues, targeting different cell types including Langerhans’ cells (LCs), dendritic cells (DCs), resting CD4+ T cells (Haase, 2011) and activated CD4+ T cells (Cohen et al., 2011).

In addition, the virus establishes latent infection in long lived resting CD4 cells (Haase, 2010).

Following the eclipse phase, the virus and/or virus-infected cells spread to other lymphoid tissues and the gut-associated lymphoid tissue (GALT) where activated CD4+CCR5+

memory T cells are found in abundance for rapid replication (McMichael et al., 2010).

Plasma viremia levels can peak at 10⁷ or more copies of viral RNA per millilitre of blood (Coffin and Swanstrom, 2013) at around 21-28 days (Haase, 2011; McMichael et al., 2010).

During this period known as peak viremia, the number of CD4+ T cells are significantly

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depleted and acute phase symptoms might appear (Haase, 2011) (Figure 1.7). The first immune response modulated by DCs and natural killer (NK) cells appear during this stage and is characterised by a large burst of inflammatory cytokines (Cohen et al., 2011). In addition, CD8+ T cell responses and non-neutralising anti-HIV antibodies (seroconversion) have also been detected at peak viremia (Gaines et al., 1988). Tomaras et al. (2008) reported the first B cell response in the form of plasma immune complexes 8 days after HIV detection and the first anti-HIV-1 antibody 13 days after the appearance of virus. Early events are critical to HIV survival and this period is considered a window of opportunity for vaccine or early intervention to prevent systemic infection (Fauci, 2007; Haase, 2011).

After peak viremia, the viral load decreases and stabilises over 21-20 weeks known as viral set point. At the same time, CD4+ T cell numbers increase to near normal concentrations in blood although counts continue to fall in the GALT. However, blood CD4+ T cell numbers begin to decline over time and is a surrogate marker for disease progression (Maartens et al., 2014). The chronic phase of infection (known also as clinical latency), can extend from 1-20 years and infected individuals can remain asymptomatic throughout (Coffin and Swanstrom, 2013). This stage is maintained by a balance between virus turnover and immune responses that limit viral replication (McMichael et al., 2010) until viremia increases and the number of CD4+ T cells declines to the point at which the immune system cannot control adventitious infectious agents (Coffin and Swanstrom, 2013).

Based on viral loads and CD4+ T cell counts, the clinical course of HIV infection was classified into three stages: 1) primary infection or acute phase of infection, when the viral load is high, 2) clinical latency, when the viral load is stable, and 3) AIDS-defining stage, where the viral load is high and host immunity is destroyed (Figure 1.7) (Mellors, 1997;

Mylonakis et al., 2001). However, the rate of disease progression is highly variable between infected individuals and they are categorised as rapid, typical (or intermediate), slow or long- term non progressors (LTNPs) (Langford et al., 2007; Pantaleo and Fauci, 1996) and EC (Zaunders and van Bockel, 2013).

Most HIV infected individuals (70-80 %) are typical progressors that follow the clinical course of infection described above. Typical progressors have long asymptomatic periods of

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clinical latency (8-10 years) with CD4+ T cell counts usually higher than 500 cells/µl (Jurriaans et al., 1994; Pantaleo and Fauci, 1996). Progression to AIDS-defining illness occurs when the CD4+ T cell counts drops and plasma viral load increases (Langford et al., 2007; Mellors, 1997; Pantaleo and Fauci, 1996; Phillips and Pezzotti, 2004). Initially, ART was introduced once CD4+ T cell levels dropped to 200 cell/ul but recently it has been debated whether ART should be initiated soon after HIV-1 infection irrespective of CD4+

levels (Ying et al., 2016). Rapid progressors on the other hand, comprising 10-15 % of infected individuals, progress to AIDS within two to three years. These individuals experience prolonged acute infection with no clinical latency transition. The CD4+ T cell counts decline very rapidly to less than 350 cell/µl within the first year of infection (Mlisana et al., 2014) with a rapid rise in viral load (between 3000 copies/mL to ≥ 300 000 copies/mL) (Langford et al., 2007). However, in LTNP, the viral load drops after acute infection and their CD4+ T cell counts remain within the normal range for several years (eight to ten) (Mandalia et al., 2012; Pantaleo and Fauci, 1996; Zaunders and van Bockel, 2013) whereas ECs suppress viral load to below detectable levels (Mandalia et al., 2012).

Variation in disease progression of HIV-1 infected individuals could be due, in part, to the genetic complexity/diversity of infecting viruses impacting the rate of disease progression (Sagar et al., 2003). Another study showed that diversification over the course of infection also influenced the rate of disease progression (Mani et al., 2002). Thus, the genetic diversity of viral populations circulating in infected individuals may play a role in determining the severity of the disease.

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Figure 1.7. Time course of HIV-1 infection and disease progression. Average HIV-1 disease progression of untreated typical progressors. CD4+ T cells are depleted progressively in the gastrointestinal tract (GIT) (green line) and remain low throughout infection while CD4+ T cells in blood (blue line) are depleted during acute phase of infection but rise again during the asymptomatic period also called “clinical latency”. HIV RNA copies (viral load) (red line) peak during acute infection and stabilise during clinical latency before rapid viral replication gives rise to a highly diverse viral population (quasispecies) when CD4+ T cells are depleted, and AIDS-defining illness appear. Graph adapted from (Maartens et al., 2014).