– Hendrik Streeck and Marcus Altfeld –
Within days of HIV-1 acquisition, a transient symptomatic illness associated with high levels of HIV-1 replication and rapid loss of CD4+ T cells occurs. This highly dynamic phase of the infection is accompanied by clinical symptoms similar to mononucleosis. However, despite an estimate of 7,000 new HIV-1 transmissions per day(UNAIDS 2010 Global Report), the diagnosis is missed in the majority of cases. Most commonly other viral illnesses (i.e., flu) are often assumed to be the cause of the symptoms, and there are no HIV-1-specific antibodies detectable at this early stage of infection. The diagnosis therefore requires a high degree of awareness and clinical knowledge based on clinical symptoms and history of exposure, in addition to specific laboratory tests (detection of HIV-1 RNA or p24 antigen and negative HIV-1 antibodies) confirming the diagnosis.
An accurate diagnosis of HIV-1 infection during this early stage of infection is particularly important as about 50% of new sexual transmissions are estimated to happen while a person is in this primary phase of infection (Brenner 2007). Indeed, phylogenetic analyses demonstrate a clustering of infections during primary HIV-1 infection, and the catalytic effect of acute HIV-1 infection on the HIV pandemic could be prevented or at least slowed by early diagnosis and immediate antiretroviral therapy intervention (see below).
Definition and classification
Acute HIV-1 infection (AHI) is defined by high levels of plasma HIV-1 RNA in the presence of a negative anti-HIV-1 ELISA and/or negative/indeterminant Western Blot (<3 bands positive) documenting the evolving humoral immune response; whereas early HIV-1 infection (EHI) includes anyone with documentation of being HIV-1–antibody negative in the preceding 6 months and is therefore broader than the definition of acute HIV-1 infection. Both are included in the term primary HIV-1 infection (PHI) (see Figure 1). Recently, a more detailed classification system of the early phases of HIV infection has been implemented (Fiebig 2003), which has rather little relevance for clinical decisions but is more important for scientific purposes. The definition used influences the methods needed to make the diagnosis and any considerations regarding the pathogenic implications of this stage of disease. Acute HIV-1 infection is often associated with an acute “retroviral syndrome” that usually includes fever with a variety of nonspecific clinical and laboratory abnormalities. In contrast, subjects with early HIV-1 infection can be asymptomatic. The time from exposure to symptomatic disease is typically 2 to 4 weeks, and the duration of illness is generally days to weeks. Identifying patients with this syndrome requires a thorough risk assessment, recognition of the variable clinical and laboratory manifestations, and understanding what tests need to be performed in order to make the diagnosis.
Signs and symptoms
Table 1: Main symptoms of acute HIV-1 infection (from Hecht 2002).
|Symptom||Frequency||Odds ratio (95% CI)|
|Oral ulcers||37%||3.1 (1.5-6.6)|
|Loss of appetite||54%||2.5 (1.2-4.8)|
|Weight loss >2.5 kg||32%||2.8 (1.3-6.0)|
|Fever and rash||46%||8.3 (3.6-19.3)|
After an incubation period ranging from a few days to a few weeks after exposure to HIV, most infected individuals present with an acute flu-like illness. Acute HIV-1 infection is a very heterogeneous syndrome and individuals presenting with more severe symptoms during acute infection and a longer duration of the acute infection syndrome tend to progress morerapidly to AIDS (Vanhems 1998, Pedersen 1989, Keet 1993). The clinical symptoms of acute HIV-1 infection were first described in 1985 as an illness resembling infectious mononucleosis (Cooper 1985). Several non-specific signs and symptoms have been reported in association with acute infection. Fever in the range of 38 to 40ºC is almost always present; in addition lymphadenopathy concomitant with the emergence of a specific immune response to HIV occurs. A generalized rash is also common in symptomatic acute HIV infection. The eruption typically occurs 48 to 72 hours after the onset of fever and persists for five to eight days. The upper thorax, collar region, and face are most affected with well-circumscribed, red colored macules or maculopapules. In addition, painful mucocutaneous oral, vaginal, anal or penal ulcerations are one of the most distinctive manifestations of the syndrome. Further common symptoms (see Table 1) are arthralgia, pharyngitis, malaise, weight loss, aseptic meningitis and myalgia (Kahn 1998). Although none of these findings are specific, several features, combinations of symptoms and prolonged duration are suggestive of HIV. The highest sensitivity for a clinical diagnosis of acute HIV-1 infection are fever (80%) and malaise (68%), whereas weight loss (86%) and oral ulcers (85%) had the highest specificity (Hecht 2002). In this study, the symptoms of fever and rash (especially in combination), followed by oral ulcers and pharyngitis had the highest positive predictive value for diagnosis of acute HIV-1 infection. In another study, fever, rash, myalgia, arthralgia and night sweats were the best predictors of acute infection (Daar 2001).
Currently, four different HIV tests are commercially available, but they have limited sensitivity in detecting acute HIV-1 infection. In order to be able to correctly interpret a positive or negative result in the presence (or absence) of acute HIV infection symptoms and corresponding history, it is important to understand differences in the sensitivities of the available tests.
The 1st and 2nd generation EIA tests are able to detect HIV-1 infection with both high specificity and sensitivity, but only after HIV-1 seroconversion, as decent levels of anti-p24 IgG antibodies need to be present to give a positive result (see Figure 1). 3rd generation EIA tests can now detect IgM antibodies and therefore are able to detect a recent infection with HIV earlier than the 1st or 2nd generation tests (Hecht 2002). The newly developed 4th generation EIA test now combines the detection of p24 antigen and p24 antibodies and therefore is able to detect HIV infection prior to seroconversion (Ly 2007). However, although this test is able to detect HIV-1 infection much earlier than all previously developed tests, a second diagnostic false negative window can occur when equal levels of p24 antigen and anti-p24 antibody are present. The most substantiated diagnosis of acute HIV-1 infection is based on the detection of HIV-1 replication in the absence of HIV-1 antibodies (pre-seroconversion). The most sensitive test is therefore based on detection of plasma HIV-1 RNA.
All assays for HIV-1 RNA that have been compared (branched chain DNA, PCR and GenProbe) have a sensitivity of 100%, but occasionally (in 2-5% of cases) lead to false positive results (Hecht 2002). False positive results from these tests are usually below 2,000 copies HIV-1 RNA per ml, and therefore are far below the high titers of viral load normally seen during acute HIV-1 infection (in our own studies subjects average 13 x 106 copies HIV-1 RNA/ml with a range of 0.25-95.5 x 106 copies HIV-1 RNA/ml). Repetition of the assay for HIV-1 RNA from the same sample with the same test led to a negative result in all false positive cases. Measurement of HIV-1 RNA from duplicate samples therefore results in a sensitivity of 100% with 100% specificity. In contrast, detection of p24 antigen has a sensitivity of only 79% with a specificity of 99.5-99.96%. The diagnosis of acute infection must be subsequently confirmed with a positive HIV-1 antibody test (seroconversion) within the following weeks.
During acute HIV-1 infection, there is frequently a marked decrease of the CD4 cell count, which later increases again, but usually does not normalize to initial levels. In contrast, the CD8 cell count rises initially, which may result in a CD4/CD8 ratio of <1. Infectious mononucleosis is the most important diagnosis to be aware of, but the differential diagnosis also includes cytomegalovirus, toxoplasmosis, rubella, syphilis, viral hepatitis, disseminated gonococcal infection, other viral infections and side effects of medications.
Figure 2: Algorithm for the diagnosis of acute HIV-1 infection.
In summary, the most important step in the diagnosis of acute HIV-1 infection is to keep it in mind during diagnosis. The clinical hypothesis of acute infection requires performance of an HIV-1 antibody test and possibly repeated testing of HIV-1 viral load, as shown in the algorithm in Figure 1 (adapted from Hecht 2002).
Immunological and virological events during acute HIV-1 infection
Transmission of HIV-1 generally results from viral exposure at mucosal surfaces followed by viral replication in submucosal and locoregional lymphoid tissues, and subsequently through overt systemic infection. The virus exponentially replicates in the absence of any detectable adaptive immune response, reaching levels of more than 100 million copies HIV-1 RNA/ml. It is during this initial cycle of viral replication that important pathogenic processes are thought to occur. These include the seeding of virus to a range of tissue reservoirs and the destruction of CD4+ T lymphocytes, in particular within the lymphoid tissues of the gut. Early on in infection, the very high levels of HIV-1 viremia are normally short-lived, indicating that the host is able to generate an immune response that can control viral replication. Over the following weeks, viremia declines by several orders of magnitude before reaching a viral setpoint. This setpoint following resolution of the acute infection is a strong predictor of long-term disease progression rates (Mellors 1995, 2007). It is therefore of critical importance to characterize and understand the immune responses induced in the initialstages of HIV-1 infectionas these first responses appear responsible for the initial control of viral replication.
In contrast to hepatitis B and C infection, acute-phase HIV replication is associated with the activationof a dramatic cytokine cascade, with plasma levels of some ofthe most rapidly induced innate cytokines peaking 7 days afterthe first detection of plasma viremia and many other cytokinesbeing upregulated as viral titers increase to their peak. Although some of the cytokines/chemokines produced inacute HIV infection may contribute to the control of viral replication,the exaggerated cytokine response likely also contributes tothe early immunopathology of the infection and associated long-termconsequences (Stacey 2009). Also, a specific activation and expansion of natural killer cells has been noted during the acute phase of infection (Alter 2007) as well as significant changes in the B cell compartment.
Several factors can influence viral replication during acute infection and the establishment of a viral setpoint. These include the fitness of the infecting virus, host genetic factors and host immune responses. While it has been shown that the transmitted/founder virus population has intact principal gene open reading frames and encodes replication-competent viruses (Salazar-Gonzalez 2009), the envelope (env) gene of elite controllers has been demonstrated to mediate less efficient entry than the envelope protein of chronic progressors (Troyer 2009). Interestingly, acute infection envs exhibit an intermediate phenotypic pattern not distinctly different from chronic progressor envs. These findings imply that lower env fitness may be established early and may directly contribute to viral suppression in elite controllers.
Antibodies against HIV-1 with neutralizing capacities are rarely detectable during primary HIV-1 infection and are therefore less likely to be major contributors to the initial control of viral replication. However, broadly neutralizing antibodies develop over time in a rare subset of HIV-infected individuals and the expression of specific markers on CD4 T cells is modestly associated with the development of these responses (Mikell 2011). In addition, several studies have demonstrated a crucial role of HIV-1-specific cellular immune responses for the initial control of viral replication. A massive, oligoclonal expansion of CD8 T cell responses has been described during acute HIV-1 infection (Pantaleo 1994), and the appearance of HIV-1-specific CD8 T cells has been temporally associated with the initial decline of viremia (Koup 1994, Borrow 1994). These CD8 T cells have the ability to eliminate HIV-1-infected cells directly by MHC class I-restricted cytolysis or indirectly by producing cytokines, chemokines or other soluble factors, thus curtailing the generation of new viral progeny (Yang 1997). The biological relevance of HIV-1-specific cytotoxic T cells (CTL) in acute HIV-1 infection was highlighted in recent in vivo studies demonstrating a dramatic rise of SIV viremia and an accelerated clinical disease progression in macaques after the artificial depletion of CD8 T cells (Schmitz 1999, Jin 1999). Additional evidence for the antiviral pressure of HIV-1-specific CTLs during primary HIV-1 infection was provided by the rapid selection of viral species with CTL epitope mutations that were detected within a few weeks of HIV-1 infection (Price 1997). A study assessing the impact of early HIV-1-specific CD8 T cell responses on the early viral set point in a cohort of over 420 subjects was able to demonstrate that the ability to mount a strong early CD8 T cell response during primary HIV-1 infection is moderately associated with a lower viral setpoint (Streeck 2009). Furthermore, the assessment of the CD8 T cell responses against autologous patient-virus-derived peptides in three subjects suggest that even more, yet undetectable, responses are present during the acute phase of the infection contributing up to 15% each to the initial control of viral replication (Goonetilleke 2009).
Many of the early immunodominant CD8 T cell responses have been shown to be restricted by HLA class I alleles, which have been previously associated with slower disease progression such as HLA-B57 or –B27. Moreover, these HLA-restricted responses preferentially target epitopes within a short highly conserved region of p24/Gag (Streeck 2007). This region encodes the HIV-1 capsid, which has been shown to be crucial for the stability of HIV-1 (Schneidewind 2007). The preservation of the early CD8 T cell responses has been associated with slower disease progression (Streeck 2009), which might be linked by the presence of HIV-1-specific CD4 T helper responses during the CTL priming process. During acute infection, the number of CD4 T cells decline, occasionally to levels that allow the development of opportunistic infections (Gupta 1993, Vento 1993). Even though the CD4 T cell count rebounds with the resolution of primary infection, it rarely returns to baseline levels in the absence of antiretroviral therapy. In addition to the decline in CD4 T cell counts, qualitative impairments of CD4 T cell function are perhaps the most characteristic abnormalities detected in HIV-1 infection. The impairment of HIV-1-specific CD4 T cell function occurs very early in acute infection (Rosenberg 1997, Lichterfeld 2004), potentially due to the preferential infection of virus-specific CD4 T cells by HIV (Douek 2002). This is followed by a functional impairment of CD4 T cell responses to other recall antigens, as well as a reduced responsiveness to novel antigens (Lange 2003). The impairment of HIV-1-specific CD4 T helper cell function in acute HIV-1 infection subsequently results in a functional impairment of HIV-1-specific CD8 T cells (Lichterfeld 2004). In addition, it has been recently shown that the induction of HIV-specific IL21+CD4+ T cells preserves and maintains the function of HIV-specific CD8 T cells (Chevalier 2011).
The contribution of the CD4 T helper response against HIV-1 is not well understood, butreports have suggested that HIV-1 can escape from CD4 T cell targeted epitopes during primary HIV-1 infection (Rychert 2009). However, as the antiviral action of CD4 T cells is most likely indirect through other effector cells, their exact contribution is difficult to measure. First studies in the lymphocytic choriomeningitis virus (LCMV-) mouse model have indicated that a strong and long-lived CD8 T cell memory response is dependent on the presence of a CD4 T cell response (Janssen 2003, Williams 2006). However, it is unknown which signals of the CD4 T cells are required for the generation and maintenance of effective HIV-1-specific CD8 T cell responses. Lack of CD4 T helper cells and chronic antigenic stimulation have been described to be the major cause of the functional deficits CD8 T cells undergo soon after the early phase of infection. This hierarchical loss of CD8 T cell function has been linked to the expression of inhibitory molecules on the cell surface of HIV-1-specific CD8 T cells such as PD-1 and several others (Day 2006, Trautmann, 2006, Blackburn 2009). The identification of such receptors might help in the generation of potential immune therapeutics to boost HIV-1-specific CD8 T cell function.
In addition to host immune responses, host genetic factors play an important role in both susceptibility and resistance to HIV-1 infection and speed of disease progression following infection. The most important of these is a deletion in the major co-receptor for entry of HIV-1 into CD4 T cells, a chemokine receptor called CCR5 (Samson 1996). Homozygotes for this 32 base pair deletion (CCR5Δ32) do not express the receptor at the cell surface and can only be infected with HIV strains that are able to use other co-receptors such as CXCR4. Thus, although CCR5delta32 homozygotic individuals show a significant degree of resistance to HIV-1 infection (Samson 1996), a number of cases of infection with CXCR4-using HIV-1 strains have been described (O’Brien 1997, Biti 1997). Heterozygotes for this deletion exhibit significantly lower viral setpoints and slower progression to AIDS. In addition to mutations in the chemokine receptor genes, a number of HLA class I alleles, including HLA-B27 and -B57, have been described to be associated with both lower viral setpoints and slower disease progression (O’Brien 2001, Kaslow 1996). Studies demonstrate that individuals expressing HLA-B57 present significantly less frequently with symptomatic acute HIV-1 infection and exhibit a better control of viral replication following acute infection (Altfeld 2003). A number of further polymorphisms have been identified that have a potential impact on HIV-1 disease progression. Here especially, the axis between detrimental immune activation and beneficial immune responses is largely unknown and part of ongoing research. For example, it has been demonstrated that polymorphisms in the IL-10 promotor region directly inhibit HIV replication, but may also promote viral persistence through the inactivation of effector immune function (Naicker 2009). These data demonstrate that host genetic factors can influence the clinical manifestations of acute HIV-1 infection and can have an important impact on the subsequent viral setpoint and the speed of disease progression.
The hypothesis of antiretroviral therapy during acute HIV-1 infection is to shorten the symptomatic viral illness, reduce the number of infected cells, preserve HIV-1-specific immune responses and possibly lower the viral setpoint in the long term. Several studies have sugggested that treatment of acute HIV-1 infection allows long-term viral suppression and might lead to a preservation and even increase of HIV-1-specific T helper cell responses.
Pilot studies in patients who are treated during acute HIV-1 infection and subsequently start treatment interruptions show that the HIV-1-specific immune response can be boosted (Rosenberg 2000, Vogel 2006, Grijsen 2011), and they experience at least temporal control of viral replication. However, other studies were not able to confirm this theoretic benefit (Markowitz 1999, Streeck 2006) and viral load rebounded during longer follow-up, requiring the eventual initiation of therapy. The theoretic benefits of early treatment must be balanced against the possible and known risks of prolonged antiretroviral therapy. These include a higher risk of accumulated long-term antiretroviral drug toxicities due to a considerable increase in the duration of antiretroviral exposure and the possibility of drug resistance if therapy fails to completely suppress viral replication.
The long-term clinical benefit of early initiation of therapy has not been demonstrated. It is also not known how long the period between acute infection and initiation of therapy can be without losing immunological, virological and clinical benefit. Thus, no recommendation for or against the initiation of antiretroviral therapy during primary HIV-1 infection can be given and needs to be decided case by case. In view of all these unanswered questions, it would be beneficial to design and enroll patients with acute HIV-1 infection in a controlled clinical trial. As a treatment option, a standard first-line treatment could be considered. It is important during counseling to clearly indicate the lack of definitive data on the clinical benefit of early initiation of antiretroviral therapy and to address the risks of antiretroviral therapy and treatment interruptions, including drug toxicity, development of resistance, acute retroviral syndrome during viral rebound and HIV-1 transmission and superinfection during treatment interruptions.
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