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The different clinical stages of HIV infection reflect patient immunological status and virological status. These two surrogate markers are currently widely used in HIV medicine to monitor progression of the infection. </p> <p> The <em>immunological status</em> is determined by the absolute (cells/ml) or relative (% lymphocytes) number of CD4+ T-cell count. </p> <p> The <em>virological status</em> is guided by the number of HIV RNA viral load expressed as copies/ml. </p> <p> The progression of the disease is influenced by several factors, such as co-infection with hepatitis B virus (HBV), hepatitis C virus (HCV) and tuberculosis (TB), viral genetic makeup, and genetic makeup of the host. </p> <ul class="keyword"> <li><span class="term">Acquisition</span> <span class="def">In approximately 80% of cases, productive infection is the result of infection with only a single virus or single virus-infected cell. Usually CCR5 coreceptor-using viral variants (<em>R5 viruses</em>) are transmitted. R5 viruses are detected at all stages of infection. </span></li> <li><span class="term">Early infection</span> <span class="def"><em>Recent HIV Infection (RHI)</em> or <em>Primary HIV Infection (PHI)</em>. During first 2 days local dissemination of virus takes place: transmission to lamina propria (loose connective tissue which lies beneath the epithelium and together with the epithelium constitutes the mucosa) via dendritic cells, CD4+ T cells, macrophages, and Langerhans cells. CD4+ memory T cells activated as a result of the infection become a specific target for R5 viruses. Some activated CD4+ T are differentiated into resting CD4+ T memory lymphocytes thus forming a reservoir of HIV infection. On third day of infection HIV-1 carrying and infected cells track to draining lymph nodes from where during the following weeks viral dissemination to distant body sites like brain, spleen, gut associated lymphoid tissue, lymph nodes, and genitourinary tract occurs. Viral spread to the gut-associated lymphoid tissue (GALT) results in increased infection of CD4+ memory effector cells and their rapid depletion. With loss of CD4+ cells in the gut, a considerable translocation of bacteria occurs across this barrier. It was also shown that lung CD4+ T cells are almost entirely lost by 21<sup>st</sup> day of infection. Thus, this period is characterized by massive depletion of CD4+ cells in organs, which does not affect CD4+ cell counts in peripheral blood. <!-- The dramatic loss of CD4+ T cells in the gut is huge in contrast to the small change in these cells in the blood. These early events result in irrepairable damage to immune system.--> Between 2 to 3 weeks after infection, in about one-half of subtype B infected individuals a mutational shift occurs in viral envelope (<em><i>Env</i></em>), which alters the viral co-receptor preference from CCR5 to CXCR4 which enables the virus to attack naïve or resting memory T cells. The emergence of <em>X4 viral variants</em> is associated with an accelerated course of the disease. Infection of the thymus occurs in the face of high CD4+ T cell regeneration requirements, resulting in thymic involution that worsens with age leading to drastic decrease in its T-cell renewal capacity. </span> <ul class="keyword"> <li><span class="term">Acute infection</span> <span class="def">Also known as <em>Primary HIV Infection (PHI)</em> and <em>Acute Retroviral Syndrome (ARS)</em>. The period is characterized by massive uncontrolled HIV replication in blood, all lymphoid tissues and particularly mucosal sites, resulting in high levels of free HIV virions circulating in the plasma (millions copies/ml). Peak plasma viral load coincides with the virus entering the central nervious system (CNS) as early as 7-21 days after infection. Antibodies are usually not yet detectable (seroconversion didn't occur). Rapid depletion of CD4+ T-cells (<em>lymphopenia</em>) can in some cases lead to transient AIDS-defining illnesses in some patients during this stage. About 40-90% of patients experience flu-like symptoms, which collectively known as <em>AIDS-related complex</em>, can include fever, inflamed lymph nodes, sore throat, and rash. The duration of the acute phase of infection is uncertain. For patients who experience compatible clinical syndrome following recent high-risk behavior, health care professionals should consider a diagnosis of acute HIV infection (both plasma HIV RNA and HIV antibody should be performed). On average, detectable plasma viremia first appears about 7 days postinfection, reaches peak concentration 7 to 10 days later, and then decreases to a steady-state, "set point" level within 8 weeks of viral acquisition The stage may last from 4 weeks to up to 6 months. </span></li> <li><span class="term">Seroconversion</span> <span class="def">Also called <em>window period</em>. The period during which a newly infected person develops antibodies to HIV. These antibodies are then detectable by second- and third-generation enzyme immunoassays (EIAs). This period varies from person to person and depends on tests that were used for detection and clade of the virus. Seroconversion may occur anywhere from days to weeks or months following HIV acquisition. The average window period is about 25 days. The mean window period is about 115-181 days after infection, which means that 50% of all infected persons develop enough antibodies to be detected by modern tests before this time and the rest 50% - after this time. By 6 months after infection, all infected persons are seroconverted. Before seroconversion occurs, HIV-1 infection can be detected by HIV-1 RNA tests which are very sensitive for PHI but false-positive results occur. Results that indicate &lt;5,000 copies/ml are considered indeterminate and require re-testing. </span></li> </ul> </li> <li><span class="term">Latency period</span> <span class="def">An asymptomatic period of ongoing viral replication and immune destruction. As the brief period of acute HIV-1 infection wanes, the immune system is faced with two problems, both caused by the viremia and both pertaining to CD4+ T cells. The first is to reconstitute depleted memory CD4+ T cell pool in the face of age-attenuated thymic output and peripheral expansion irrespective of ongoing viral replication. The second problem is that the viral replication, in its turn, aggravates those renewal limitations by further impairing lymphopoietic sources (thymus and lymph nodes), and inducing chronic CD4+ T cell activation that drives the virus propagation and kills the cells placing additional strain on maintenance of the "resting" naive and memory CD4+ T cell pools. Eventual development of HIV-specific immune responses as well as the rapidly diminishing availability of activated CD4+ T cell substrates leads to a rapid fall in HIV-1 load after acute infection. This quasi-stable steady state often takes months to become established, usually preceded by a period of strong viral load fluctuations. Gradually, the plasma viral load decreases to the range of 20,000-60,000 copies/ml and remains more or less steady at a concentration that is known as the <em>viral set point</em>. As a rule, the higher the vial set point, the faster infection's progress. A large study found that patients with viral set points greater than 100,000 copies/ml were 10 times more likely to progress to AIDS within 5 years than those with lower viral set points. The level of the HIV viral set point depends on many factors, including viral pathogenicity and the patients' innate immune status and genetic makeup. After the establishment of viral set point, a limited period of stability between HIV replication and the body's immune response to the virus develops. Because their CD4+ T-cell count remains stable and within the normal range, patients feel relatively well during this period. This stage of infection lasts on average between 8 and 10 years. During this time, the virus undergoes an evolution. In order to infect the target cell the virus requires attachment to CD4 receptors that are expressed on the surface of the cellular membrane. It is now known that HIV also needs a chemokine co-receptor adjacent to the CD4 receptor. Two types of chemokine co-receptors are used by HIV: <em>CCR5</em> (a b-chemokine receptor) and <em>CXCR4</em> (an a-chemokine receptor). Early in HIV infection, the virus is a nonsyncytial- inducing variant with tropism towards CCR5 receptors (<em>R5-tropic</em>). Non-syncytial-inducing viruses do not induce fusion of T cells (<em>syncytium formation</em>) <i>in vitro</i>. They grow relatively slowly, and grow equally well in monocytes and lymphocytes. At later stages of infection, the virus switches to a syncytial-inducing variant with tropism towards CXCR4 receptors (<em>X4-tropic)</em>. Syncytial-inducing viruses grow more rapidly <i>in vitro</i> than nonsyncytial- inducing viruses. Their emergence presages the imminent decay of CD4+ T cells and rapid progress of the disease to AIDS. In any infected patient, there are swarms of viruses with different tropism towards the two different chemokine co-receptors. </span></li> <li><span class="term">Late infection</span> <span class="def">This stage occurs when the host's immune system is immunocompromised to such a degree that without an initiation of <em>Highly Active Anti-Retroviral Therapy (HAART)</em> the infection is going to progress to <em>Acquired Immunodeficiency Syndrome (AIDS)</em> at rapid pace. </span> <ul class="keyword"> <li><span class="term">Acquired <br /> Immunodeficiency <br /> Syndrome (AIDS)</span> <span class="def">AIDS is characterized by the death of CD4+ cells, which leaves the body vulnerable to life-threatening conditions, such as opportunistic infections and cancers. AIDS occurs in individuals that do not receive <em>HAART</em> (Highly Active ANti-Retroviral Therapy) or in case of <em>Immunologic Failure</em> (when HAART regimen failed). According to the Centers for Disease Control's (CDC) 1993 standards, an HIV-infected individual has AIDS when either (a) their CD4+ cells fall to fourteen percent or less of total lymphocytes, or (b) when the CD4+ count is less than 200 cells/¼l or (c) when at least one of a specific set of opportunistic infections or neoplasms occurs (Centers for Disease Control and Prevention 1992). When the absolute CD4þ T-cell count falls to &lt;200 cells/ml, patients become susceptible to opportunistic infections and certain neoplasms each of which is defined as <em>AIDS-Defining Condition</em>. The 26 conditions include: </span> <ul class="keyword"> <li><span class="term">AIDS dementia complex</span></li> <li><span class="term">Candida of the esophagus, trachea, bronchi and lungs</span></li> <li><span class="term">Coccidiodomycosis</span></li> <li><span class="term">Cryptosporidiosis</span></li> <li><span class="term">Cytomegalovirus infection (excluding liver, spleen, lymph nodes)</span></li> <li><span class="term">Herpes simplex virus (HSV) lasting more than 1 month, or esophageal HSV</span></li> <li><span class="term">Histoplasmosis</span></li> <li><span class="term">Invasive cervical carcinoma</span></li> <li><span class="term"><i>Isospora beli</i></span></li> <li><span class="term">Kaposi's sarcoma</span></li> <li><span class="term">Lymphoma: Burkitt's, immunoblastic, primary CNS</span></li> <li><span class="term">Mycobacterial infection</span></li> <li><span class="term"><i>Pnemocystis jiroveci</i></span></li> <li><span class="term">Pneumonia: recurrent within 12 months</span></li> <li><span class="term">Progressive multifocal leukoencephalopathy</span></li> <li><span class="term">Salmonella sepsis</span></li> <li><span class="term">Toxoplasmosis of the brain</span></li> <li><span class="term">Wasting syndrome</span></li> </ul> </li> <li><span class="term">Infection <br /> suppressed<br /> with HAART</span> <span class="def">Current HIV treatment guidelines suggest starting combination antiretroviral therapy (cART) only in patients with advanced disease as defined by specific criteria that are revised on an annual basis. HIV replication is measured by quantifying the viral load, defined as the number of viral RNA copies per milliliter of blood plasma. Patients who maintain good adherence to cART often achieve reduction of the viral load to undetectable levels, curbing the destruction of CD4+ T lymphocytes, but not eradicating the virus which reemerges in nearly all patients when cART is stopped. As these lymphocytes repopulate their numbers, the immune system regains strength. Thus cART frequently results in substantial immune reconstitution in HIV-infected individuals. After start of HAART, the virus in the active CD4+ T cells becomes suppressed in two phases: </span> <ul class="keyword"> <li><span class="term">Early phase</span> <span class="def">An early rapid phase that occurs after a period of 2-3 months of the start of HAART. The early phase of viral suppression is manifested by significant drop in plasma HIV RNA viral load count. </span></li> <li><span class="term">Stable phase</span> <span class="def">A more gradual delayed phase. However, viral replication in the latently infected lymphocytes and monocytes, and in antigen-presenting cells, takes longer to suppress. It has become apparent that this second viral reservoir becomes nearly fully suppressed after more than 6 months of having plasma HIV RNA viral load of &lt;50 copies/ml.</span> </li> </ul> </li> </ul> </li> </ul> <a href="#top">Back to top</a> <img src="../IMG/Nemose-ruler.png" alt="Nemose" /> <!--GOOGLE SEARCH--> <!--GOOGLE SEARCH--> <h4> Mechanisms for CD4+ cell loss</h4> <ul class="genInfo"> <li>Direct cytopathic effect of viral infection</li> <li>Chronic immune activation causing activation of apoptotic pathways</li> <li>Antibody-dependent cellular cytotoxicity (ADCC) induced by antibody recognition of CD4+ cells carrying gp120</li> <li>Cytotoxic T limphocyte (CTL) activity against normal CD4+ cells</li> <li>Lack of lymphocyte regeneration due to damages to hematopoeitic system</li> </ul> <!--supplement early disease--> <h4> Immune Reconstitution Inflammatory Syndrome (IRIS)</h4> <p> Also known as <em>Immune Restoration Disease</em> (IRD). The immune reconstitution inflammatory syndromes (IRIS) is a serious problem complicating the treatment of AIDS. IRIS refers to a group of syndromes characterized by paradoxical clinical worsening that usually occurs within the first 4 to 8 weeks after starting cART. Fever, along with swelling, redness, or discharge at the site of an injury or infection, may signal that an infection that was previously unnoticed by a weak immune system is now a target of a stronger immune system. This exaggerated "dysregulated" inflammatory response is characterized by massive infiltration of CD81 cells. Although IRIS indicates that a person's immune system improves, it can be a serious, sometimes fatal condition especially when Central Nervous Systems is involved. Among the most common CNS complications reported to be involved in IRIS are HIV encephalitis, Progressive Multifocal Leukoencephalopathy (PML), Most patients survive the syndrome. Some studies have reported both active lesions containing the pathogen (HIV-associated multinucleated giant cells, Toxoplasma parasites, etc), and "sterile" lesions with inflammatory infiltrates. The treatment of CNS IRIS with corticosteroids has been advocated and remains controversial. </p> <a href="#top">Back to top</a> <img src="../IMG/Nemose-ruler.png" alt="Nemose" /> <p> <em>Viral load (VL) dynamics and CD4+ cell count are presented by red and blue curve respectively. HAART therapy started when CD4+ count dropped lower than 350 cells/ml. At that time viral load was still at its setting point of about 10,000 copies/ml. Without the therapy CD4+ cells count would continue to decrease rapidly accompanied by moderate but steady VL increase leading to immune system's collapse, AIDS and patient's death within next 1-3 years.</em> </p> <img src="../IMG/hiv-viral-load-dynamics-2.png" alt="HIV viral load dymamics, untreated and treated" /> <a href="#top">Back to top</a> <img src="../IMG/Nemose-ruler.png" alt="Nemose" /> <!--GOOGLE SEARCH--> <!--GOOGLE SEARCH--> <h4> Literature</h4> <ul> <li> <p> Coleman CM, Wu L. <em>HIV interactions with monocytes and dendritic cells: viral latency and reservoirs.</em> <a class="external" target="_blank" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2697150/?tool=pubmed" title="Review"><i>Retrovirology. 2009 Jun 1;6:51.</i></a> </p> <p class="centered"> <img src="../IMG/HIV-1-latency.jpg" alt="HIV-1 latency" /> </p> <p> <em>Locations of HIV-1 replication and latency and routes of transmission between haematopoietic cell populations.</em> All cell types shown are susceptible to HIV-1 entry and integration of the proviral DNA. Some anatomical locations are shown; those outside of marked areas are in the bloodstream, lymphatic system and/or tissues. Black arrows represent differentiation and/or maturation and may represent more than one step and could involve multiple intermediate cell types. Purple arrows represent routes of trans infection, and relative rates are shown as high or low. "Rep" indicates productive HIV-1 replication with relative rates shown as high or low. HIV-1 cis infection routes are not shown, as any susceptible cell may be infected by productive replication from another cell. Those cells in which HIV-1 latency is thought to occur should be considered as putative viral reservoirs and therapeutic targets. </p> </li> <li> <p> van der Kuyl AC, Cornelissen M. <em>Identifying HIV-1 dual infections.</em> <a class="external" target="_blank" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2045676/?tool=pubmed" title="Review"><i>Retrovirology. 2007 Sep 24;4:67.</i></a> </p> <p class="centered"> <img src="../IMG/HIV-1-viral-load.jpg" alt="HIV-1 viral load at different clinical stages" /> </p> <p> <em>HIV-1 plasma viral load at different clinical stages.</em> HIV infection is characterized by an acute phase with a high viral load, which decreases as specific immunity develops (solid line). After seroconversion (SC), the chronic phase of the infection starts, lasting several years. The chronic phase of the infection is traditionally followed by the AIDS phase, but is now increasingly replaced by the start of antiretroviral therapy (ART) in many parts of the world. An HIV-1 dual infection during the acute phase is called a co-infection, after seroconversion it is referred to as a superinfection. HIV-1 superinfections often result in an increase, sometimes temporary, of the viral load (dotted line) and an earlier start of therapy. HIV-1 superinfections in most cases are found close to the acute infection, and only rarely occur later than a few years after primary infection. </p> </li> </ul> <a href="#top">Back to top</a> <img src="../IMG/Nemose-ruler.png" alt="Nemose" /> <!-- SHOULD GO TO HAART--> <div class="centered"> <script type="text/javascript"> ch_client = "nemose"; ch_width = 500; ch_height = 250; ch_type = "mpu"; ch_sid = "metapathogen"; ch_color_site_link = "#0000CC"; ch_color_title = "#0000CC"; ch_color_border = "#FFFFFF"; ch_color_text = "#000000"; ch_color_bg = "#FFFFFF"; </script> <script src="http://scripts.chitika.net/eminimalls/amm.js" type="text/javascript"> </script> <!--chitika AD--> </div> <div> <!-- Kontera ContentLink(TM);--> <script type='text/javascript'> var dc_AdLinkColor = 'blue' ; var dc_PublisherID = 79943 ; </script> <script type='text/javascript' src='http://kona.kontera.com/javascript/lib/KonaLibInline.js'> </script> <!-- Kontera ContentLink(TM) --> </div> <div class="centered"> <p> &nbsp;</p> <!--SPOTBACK--> <!-- get your own widget at http://spotback.com <script src='http://spotback.com/scripts/widgets/load.js?wid=48994'></script> <noscript> <a href="http://spotback.com" alt="Rate everything widget"> <img src="http://spotback.com/images/rating.gif" alt="user rating" /></a></noscript>--> <!--SPOTBACK--> <p> &nbsp;</p> </div> <div class="centered"> <p> &nbsp;</p> <!--letsgodynamic--> <!-- div3009677894 --> <script type="text/javascript" src="http://letsgodynamic.com/sm-vidm/dispatcher/call.js.php?lang=EN&clientid=SCLNT018fed78ed96a284ed5414e265e37af2"></script> <div id="div3009677894"> <script type="text/javascript">request_send('SVIEW435329efa7a685c494f90bfdb53f4182','viewclientid=SCLNT018fed78ed96a284ed5414e265e37af2&globalid=3009677894','div3009677894','div3009677894');</script> <a href="http://letsgodynamic.com">D-Modules: Comment service</a></div> <!--letsgodynamic--> <p> &nbsp;</p> </div> <!-- <div> <p class="emphasis"> Please link to this page using the code in the text area. 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